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下圖中這里所謂的物品可變，更多的實(shí)踐是滅菌物品數(shù)量可變（滅菌物品本身以及擺放位置不可變），今天分享的是PDA Journal上的一些思路。
Flexible Loading Pattern Approach in Overkill Steam Sterilization Based on the Physical Properties of Steam and Thermodynamics of Sterilization
基于蒸汽的物理特性和滅菌熱力學(xué)的過(guò)度殺菌蒸汽滅菌中的靈活裝載模式方法。
ABSTRACT: Because overkill steam sterilization processes in autoclaves are considered critical, they are highly scrutinized, and the use of autoclaves in fixed loading patterns is a common approach to the interpretation of regulatory requirements. Many such regulations are attributed to tradition and a buildup of restrictions that aim to improve the levels of assurance of the process and minimize risk. However, these measures complicate the operation and qualification of autoclaves, becoming cumbersome, time-consuming, and costly. In actuality, overkill sterilization is one of several processes in the pharmaceutical industry that provides the highest levels of sterility assurance. This method provides a minimum reduction of highly durable spore populations of 12 logs, achieving a probability of a nonsterile unit (PNSU) of 10-6. The physical properties of steam and the thermodynamics of steam sterilization constitute a predictable and repeatable process that can be monitored and verified. The high assurance level of overkill sterilization, combined with the properties of steam, actualizes a high safety margin that encompasses nearly every load type and load configuration when the cycle is performed under certain basic rules. The aim of this article is to present data that advocate and favor an approach that allows greater freedom and variability in arranging items in an autoclave when running overkill cycles, without the need to qualify each configuration.
摘要：因?yàn)楦邏赫羝麥缇^(guò)程在滅菌器中被視為關(guān)鍵過(guò)程，它們受到嚴(yán)格的審查，使用固定裝載模式的滅菌器是解釋監(jiān)管要求的常見方法。許多這樣的規(guī)定歸因于傳統(tǒng)和限制的積累，旨在提高過(guò)程的保證水平并將風(fēng)險(xiǎn)降至最低。然而，這些措施使滅菌器的操作和確認(rèn)復(fù)雜化，變得笨重，耗時(shí)，昂貴。實(shí)際上，過(guò)度殺滅法是制藥工業(yè)中提供最高無(wú)菌保證水平的幾個(gè)過(guò)程之一。這種方法至少能將非常耐用的孢子群體減少12個(gè)logs，從而實(shí)現(xiàn)非無(wú)菌單元（PNSU）的概率為10−6。蒸汽的物理性質(zhì)蒸汽滅菌的熱力學(xué)構(gòu)成了一個(gè)可預(yù)測(cè)和可重復(fù)的過(guò)程，可以監(jiān)控和驗(yàn)證。過(guò)度殺菌的高保證水平結(jié)合蒸汽的特性，在遵循一定基本原則的情況下，實(shí)現(xiàn)了一個(gè)高安全邊際，幾乎涵蓋了所有類型的裝載和裝載配置。本文的目的是提出數(shù)據(jù)，支持并傾向于一種方法，該方法在運(yùn)行過(guò)度殺菌周期時(shí)，允許在高壓蒸汽滅菌器內(nèi)安排物品時(shí)有更大的自由度和可變性，無(wú)需對(duì)每種配置進(jìn)行驗(yàn)證。
1、在安全邊際的更安全一側(cè)
On the Safe Side of Safe Side
Overkill Cycles 過(guò)度殺滅周期
Steam sterilization is one of the most common and important practices in parenteral manufacturing, bound by many rules and regulations. In a routine inspection, the validation, maintenance, and operation of an autoclave are usually examined thoroughly. Without downgrading the criticality of steam sterilization, many requirements are derived from the definition of “critical”, even when there is no scientific basis for the requirements. In other cases, the requirements are extended far beyond what is really needed to be “on the safe side”.
蒸汽滅菌是輸液制造中一種最常見且重要的實(shí)踐，受到許多規(guī)則和法規(guī)的約束。在常規(guī)檢查中，通常會(huì)對(duì)高壓蒸汽滅菌器的驗(yàn)證、維護(hù)和操作進(jìn)行徹底的檢查。在不降低蒸汽滅菌關(guān)鍵性的前提下，許多要求源自“關(guān)鍵”一詞的定義，即使這些要求沒(méi)有科學(xué)依據(jù)。在其他情況下，為了“更安全”，要求被擴(kuò)展到了真正需要的范圍之外。
The rationale of the overkill cycle was that it would allow more flexibility in sterilization, due to the high safety margins that it provides to compensate for potential variation in this process. The premise of overkill cycles is that the bioburden population and its resistance can be ignored, because they are irrelevant to the outcome. This genuine benefit is eliminated, because in actuality, overkill sterilization cycles are restricted by additional regulatory requirements and “expectations” to inflate the safety margin. The requirement for fixed loading patterns is one of the most burdensome of these principles.
過(guò)度殺菌周期的原理是，由于它提供了很高的安全邊際來(lái)彌補(bǔ)過(guò)程中可能出現(xiàn)的變化，因此它將允許在滅菌中有更多的靈活性。過(guò)度殺菌周期的前提是，可以忽略生物負(fù)荷的種群數(shù)量和其抗性，因?yàn)檫@些與結(jié)果無(wú)關(guān)。這種真正的好處被消除了，因?yàn)樵诂F(xiàn)實(shí)中，過(guò)度殺菌周期受到額外的監(jiān)管要求和“期望”的限制，這些要求和期望增加了安全邊際。固定裝載模式的要求是這些原則中最繁重的一個(gè)。
2、固定裝載模式的要求
Requirements of Fixed Loading Patterns
In a fixed loading pattern, the items that are to be sterilized are arranged according to a scheme or depiction that shows their exact number, size, position, and orientation in the chamber. This arrangement is validated, and if all the acceptance criteria are met, the load is approved for production. If a new item is added to a validated load, the load is considered to be new, and the validation must be repeated. The same process applies to items that have been validated in other loads and, due to changing production requirements,must now be sterilized with other items in a different load
在固定裝載模式中，待滅菌的物品根據(jù)方案或圖示所展示的它們的確切數(shù)量、大小、位置和方向在腔室內(nèi)進(jìn)行排列。這種排列方式經(jīng)過(guò)驗(yàn)證，一旦滿足所有接受標(biāo)準(zhǔn)，裝載量就會(huì)被批準(zhǔn)用于生產(chǎn)。如果向經(jīng)過(guò)驗(yàn)證的裝載量中添加了新物品，則該裝載量被視為新的裝載量，必須重新進(jìn)行驗(yàn)證。同樣的過(guò)程也適用于那些在其他裝載量中已經(jīng)經(jīng)過(guò)驗(yàn)證的物品，由于生產(chǎn)需求的變化，現(xiàn)在必須與其他物品一起在不同的裝載量中進(jìn)行滅菌。
The roots of this method date back to the 1970s, when many practices that were related to large-volume parenteral (LVP) sterilization were universally adopted by the small-volume parenteral (SVP) industry, regardless of their use in a different setting (5). At that time, when gravity displacement autoclaves were used in many facilities, this principle was justified. Since then, autoclave design has evolved considerably, with the advent of vacuum and steam pulses to remove air from porous loads and greater control over temperature and pressure in the chamber. In contrast, validation practices have remained almost unchanged.
這種方法的根源可以追溯到20世紀(jì)70年代，當(dāng)時(shí)許多與大容量腸外（LVP）滅菌相關(guān)的實(shí)踐被小容量腸外（SVP）行業(yè)普遍采納，而不管它們?cè)诓煌O(shè)置中的使用情況。當(dāng)時(shí)，許多設(shè)施使用的是依靠重力置換的滅菌器，這一原理在當(dāng)時(shí)是合理的。從那時(shí)起，隨著真空和蒸汽脈沖技術(shù)的出現(xiàn)，用于從多孔負(fù)載中去除空氣，以及對(duì)腔室內(nèi)溫度和壓力的更嚴(yán)格控制，滅菌器的設(shè)計(jì)已經(jīng)發(fā)生了顯著的演變。相比之下，驗(yàn)證實(shí)踐幾乎沒(méi)有任何變化。
In certain firms, only exact, validated loads are allowed to be run—if for example, just 1 of the 20 items that are validated in the full load is needed, the entire load must be prepared (i.e., washed, bagged, and arranged) and sterilized. To this end, some firms use maximal and minimal load cycles (Max-Min approach), which provides more flexibility. But, when a new item isrequired or validated loads must be combined, the new load needs to be validated again before use
在某些公司，只允許運(yùn)行確切經(jīng)過(guò)驗(yàn)證的裝載量——例如，如果只需要運(yùn)行已在完整裝載量中驗(yàn)證的20個(gè)項(xiàng)目中的1個(gè)，那么必須準(zhǔn)備整個(gè)裝載量（即，洗滌、包裝并排列）并進(jìn)行滅菌。為此，一些公司使用最大和最小裝載周期（最大-最小方法），這提供了更多的靈活性。但是，當(dāng)需要一個(gè)新的項(xiàng)目或必須組合經(jīng)過(guò)驗(yàn)證的裝載量時(shí)，新的裝載量在使用前需要重新驗(yàn)證。
The requirement for fixed loading patterns is triggered by the belief that there is an interaction between items, that one item can influence or interact with an adjacent item, and that the item per se might not be sterilized in a different area in the autoclave—that is, that items can “steal” steam from other items, creating a cold spot or restricting steam flow to other items. For example,heavy items could be believed to be “steam-consuming” items that reduce the supply of steam to other items. This suspicion then leads to the requirement that many loading patterns be validated and maintained through revalidation activities.
固定裝載模式的要求源于這樣一種信念：物品之間存在相互作用，一個(gè)物品可能會(huì)影響到相鄰物品，或者物品本身在高壓蒸汽滅菌器的不同區(qū)域可能不會(huì)被滅菌——也就是說(shuō)，物品可能會(huì)從其他物品那里“搶奪”蒸汽，從而制造出冷點(diǎn)或限制蒸汽流向其他物品。例如，人們可能認(rèn)為重量較大的物品是“消耗蒸汽”的物品，它們減少了對(duì)其他物品的蒸汽供應(yīng)。這種懷疑隨后導(dǎo)致了要求對(duì)許多裝載模式進(jìn)行驗(yàn)證，并通過(guò)對(duì)重新驗(yàn)證活動(dòng)來(lái)維持。
The standard validation procedure that is used by certain firms is to run three distribution cycles and three penetration cycles for each new load, rendering the workload and downtime of the facility to be significant and costly. Reducing nonvalue-added validation activities can create significant savings for facilities, with no adverse impact on patient safety.
某些公司使用的標(biāo)準(zhǔn)驗(yàn)證程序是對(duì)每個(gè)新裝載量運(yùn)行三個(gè)分布周期和三個(gè)穿透周期，這使得設(shè)施的工作量和停機(jī)時(shí)間都相當(dāng)大且成本高昂。減少不增加價(jià)值的驗(yàn)證活動(dòng)可以為設(shè)施創(chuàng)造顯著的節(jié)省，且不會(huì)對(duì)患者安全產(chǎn)生負(fù)面影響。
This article will attempt to challenge this difficult question with data and convincing arguments, suggesting an approach that allows greater freedom and variability in arranging items in an autoclave when running overkill cycles, without the need to qualify each configuration or any adverse impact on patient safety or the required sterility assurance levels.
這篇文章將嘗試用數(shù)據(jù)和有說(shuō)服力的論點(diǎn)挑戰(zhàn)這個(gè)難題，提出一種方法，允許在運(yùn)行過(guò)度殺菌周期時(shí)，在高壓蒸汽滅菌器內(nèi)安排物品時(shí)有更大的自由度和可變性，而無(wú)需對(duì)每個(gè)配置進(jìn)行驗(yàn)證，也不會(huì)對(duì)患者安全或所需的無(wú)菌保證水平產(chǎn)生任何負(fù)面影響。
3、飽和蒸汽的物理性質(zhì)和滅菌熱力學(xué)
Physical Properties of Pure Saturated Steam and the Thermodynamics of Sterilization
Steam sterilization relies on the physical properties of pure saturated steam and the thermodynamics of the sterilization process. Any claim that relates to the ability of steam to sterilize should be evaluated in light of its properties, as described following.
蒸汽滅菌依賴于飽和純蒸汽的物理特性和滅菌過(guò)程的熱力學(xué)原理。任何與蒸汽滅菌能力相關(guān)的主張都應(yīng)該基于其特性來(lái)評(píng)估，具體特性如下
1. Steam releases a large amount of energy relative to its weight when it condenses. A small amount of steam can heat a large load, as well as the metal structure of the autoclave. As it condenses, 1 kg of saturated steam releases 2200 kJ, which, when condensed, can heat over 40 kg of stainless steel (SS) from 20?C to 121?C ; thus, heating “heavy” metal items does not require large amounts of steam.
1.蒸汽在凝結(jié)時(shí)相對(duì)于其重量釋放出大量的能量。少量的蒸汽就能加熱大量的負(fù)載，包括滅菌器的金屬結(jié)構(gòu)。當(dāng)1公斤的飽和蒸汽凝結(jié)時(shí)，它釋放出2200千焦的能量，這足以將40公斤以上的不銹鋼從20 ?C加熱到121 ?C；因此，加熱“重”金屬物品并不需要大量的蒸汽。
2. When saturated steam is condensed, its volume decreases significantly (1 L of saturated steam turns into approximately 1.2 mL of condensate) .
Whenever condensation occurs (when steam makes contact with cold areas and condenses), the reduction in volume will bring more steam to cold sections due to the decrease in pressure until the item reaches the same temperature as the steam and no further heating is needed.
2.當(dāng)飽和蒸汽凝結(jié)時(shí)，其體積顯著減少（1升飽和蒸汽大約轉(zhuǎn)變?yōu)?.2毫升的凝結(jié)水）。每當(dāng)發(fā)生凝結(jié)（即蒸汽接觸到冷的區(qū)域并凝結(jié)時(shí)），由于壓力降低，體積的減少會(huì)將更多蒸汽帶到冷的區(qū)域，直到物品加熱到與蒸汽相同的溫度，此時(shí)不再需要進(jìn)一步加熱。這一過(guò)程有助于確保蒸汽滅菌過(guò)程中所有物品都能均勻地達(dá)到滅菌所需的溫度。
3. There is a 1:1 correlation between saturated steam pressure and its temperature in an enclosed space with constant volume. After the pressure stabilizes, temperatures in the chamber become steady and will be maintained throughout the chamber as a result of the stabilization of pressure.
3.在恒定體積的封閉空間內(nèi)，飽和蒸汽的壓力與其溫度存在1:1的相關(guān)性。壓力穩(wěn)定后，腔室內(nèi)的溫度變得穩(wěn)定，并且由于壓力的穩(wěn)定，腔室內(nèi)的溫度將保持一致。
4. Steam that is under pressure in an enclosed space does not flow like air; thus, there are no steam flow patterns in the autoclave. Items do not obstruct steam or prevent it from entering other objects. Providing a load does not block the passage of steam completely—steam will reach all items. As indicated in Point 2, whenever condensation arises, the steam that is nearest to the condensation point will move toward it. These movements occur on a molecular level and are thus rapid; consequently, steam molecules are not influenced by the other items. Combining this inherent property of steam with the property in Point 3 ensures that wherever items are positioned in the chamber, each element will be subjected to the same sterilization conditions. The only interaction that might occur between items is the condensate, which can drip from heavy nonporous items onto lower items; this situation can be resolved easily by placing the former on the lower shelf of the autoclave.
4.在封閉空間中加壓的蒸汽不會(huì)像空氣那樣流動(dòng)；因此，在高壓蒸汽滅菌器內(nèi)不存在蒸汽流動(dòng)模式。物品不會(huì)阻礙蒸汽或阻止其進(jìn)入其他物體。即使裝載了物品，也不會(huì)完全阻塞蒸汽的通道——蒸汽能夠到達(dá)所有物品。如第2點(diǎn)所述，每當(dāng)發(fā)生凝結(jié)時(shí)，最接近凝結(jié)點(diǎn)的蒸汽會(huì)向其移動(dòng)。這些運(yùn)動(dòng)發(fā)生在分子層面上，因此速度很快；因此，蒸汽分子不會(huì)受到其他物品的影響。結(jié)合蒸汽的這一固有屬性和第3點(diǎn)所述的屬性，可以確保無(wú)論物品在腔室內(nèi)如何定位，每個(gè)元素都將受到相同的滅菌條件。物品之間可能發(fā)生的唯一交互是凝結(jié)水，它可能從重量較重的非多孔物品滴落到下方的物品上；通過(guò)將前者放置在高壓蒸汽滅菌器的下層架上，可以輕松解決這種情況。
5. Heat can be transferred between objects only when there is a difference in temperature. Once the items in the autoclave attain the temperature of the steam, no more energy is transferred to the item, and further condensation stops—an equilibrium is reached. Additional small quantities of steam enter the autoclave only to compensate for the heat loss to the doors and chamber walls (even when the jacket is heated, because the temperature of the jacket is lower than that of the chamber).
5.只有在存在溫度差時(shí)，物體之間才能傳遞熱量。一旦滅菌器內(nèi)的物品達(dá)到蒸汽的溫度，就不會(huì)再向物品傳遞更多的能量，進(jìn)一步的凝結(jié)就會(huì)停止——達(dá)到了平衡。少量的蒸汽進(jìn)入滅菌器只是為了補(bǔ)償對(duì)門和腔室壁的熱損失（即使滅菌器的外層被加熱，因?yàn)橥鈱拥臏囟热匀坏陀谇皇业臏囟?，腔室?nèi)的蒸汽仍需補(bǔ)充，以確保滅菌過(guò)程中溫度的均勻性和一致性）。
6. After an equilibrium is reached (after the heating phase and at the outset of the sterilization phase), pressure across the chamber will be equal, according to Pascal’s law.
6.達(dá)到平衡后（在加熱階段之后和滅菌階段開始時(shí)），根據(jù)帕斯卡定律，腔室內(nèi)的壓力將是均勻的。
7. Steam and air (primarily nitrogen and oxygen) are small molecules (>1 nm); thus, air removal and steam penetration can also be achieved through narrow channels or gaps. Large quantities of steam require wider passageways, but even with small gaps, steam will eventually penetrate all parts of an object.
7.蒸汽和空氣（主要是氮?dú)夂脱鯕猓┒际切》肿樱ㄖ睆酱笥?納米）；因此，即使通過(guò)狹窄的通道或縫隙，也能實(shí)現(xiàn)空氣的移除和蒸汽的滲透。大量的蒸汽需要更寬的通道，但即使存在小的縫隙，蒸汽最終也會(huì)滲透到物體的所有部分。
With regard to load, other physical properties are involved in steam sterilization. Table I lists the load properties of items and their effects on sterilization. Combining these properties simplifies the decision over which items are easy or more challenging to sterilize. Table II lists examples of common items. Note that the table merely compares items and does not definitively state whether an item is challenging for an overkill cycle.
在蒸汽滅菌中，與裝載量相關(guān)的其他物理屬性也起著重要作用。表I列出了物品的裝載屬性及其對(duì)滅菌的影響。結(jié)合這些屬性可以簡(jiǎn)化判斷哪些物品容易或更具挑戰(zhàn)性進(jìn)行滅菌的決策過(guò)程。表II列出了一些常見物品的例子。需要注意的是，該表僅比較了物品，并沒(méi)有明確指出某個(gè)物品對(duì)于過(guò)度殺菌周期是否具有挑戰(zhàn)性
In summary：總結(jié)如下
1. Steam can heat a heavy load at low quantities due to high latent heat of condensation (Point 1). Fresh steam will fill the low-pressure zones that are created due to condensation (Point 2), supplying more energy. Heavy loads might elongate the heating phase, but this extra time is not included in the sterilization phase time. Eventually, after the load reaches the sterilization temperature, there is no difference between heavy and light loads, because there is no further transfer of energy to the load (Point 5). Mass should not be the chief parameter for selecting challenging items. The results of the tests in Pavell and Hughes (9) also showed that the more challenging items were the filter and the cleaning hose with a valve on one end, neither of which was among the heaviest items.
1.蒸汽的高凝結(jié)潛熱使其即使在數(shù)量較少的情況下也能加熱質(zhì)量大的負(fù)載。新鮮的蒸汽將填補(bǔ)由于凝結(jié)而產(chǎn)生的低壓區(qū)域，提供更多的能量。沉重的負(fù)載可能會(huì)延長(zhǎng)加熱階段，但這個(gè)額外的時(shí)間不包括在滅菌階段的時(shí)間之內(nèi)。最終，在負(fù)載達(dá)到滅菌溫度后，重負(fù)載和輕負(fù)載之間沒(méi)有區(qū)別，因?yàn)閷?duì)負(fù)載沒(méi)有進(jìn)一步的能量傳遞。質(zhì)量不應(yīng)是選擇具有挑戰(zhàn)性物品的主要參數(shù)。Pavell和Hughes的測(cè)試結(jié)果也表明，更具挑戰(zhàn)性的物品是過(guò)濾器和一端帶閥門的清潔軟管，這兩者都不是最重的物品。
2. One of the most common myths that concern steam sterilization is that the high lethality of steam is attributed to the high energy transfer to the sterilized object during condensation (13): “Direct steam contact with the surface of the object to be sterilized is required for the steam to transfer its stored energy to the object.” Direct contact is definitely required, because the moisture in the steam must make contact with the item, but the last section of this statement becomes irrelevant when the setpoint temperature has been attained by all load items. As indicated in Point 5, energy transfer occurs only during the heating phase; throughout the sterilization phase, there is no energy transfer, and microorganisms are eradicated by maintaining the temperature and water molecules contact for the required time
2.關(guān)于蒸汽滅菌的一個(gè)常見誤解是，蒸汽的高致命性歸因于在凝結(jié)過(guò)程中對(duì)被滅菌物體的高能量傳遞：“蒸汽必須與被滅菌物體的表面直接接觸，才能將其儲(chǔ)存的能量傳遞給物體。” 直接接觸絕對(duì)是必需的，因?yàn)檎羝械乃直仨毰c物品接觸，但當(dāng)所有負(fù)載項(xiàng)目達(dá)到設(shè)定溫度時(shí)，這一說(shuō)法的后半部分就變得無(wú)關(guān)緊要了。能量傳遞僅在加熱階段發(fā)生；在整個(gè)滅菌階段，沒(méi)有能量傳遞，微生物是通過(guò)維持溫度和水分子接觸所需時(shí)間來(lái)根除的。
3. From Points 2, 4, 6, and 7, I conclude that there is no impact of the location of items in the autoclave with regard to achieving the same extent of sterilization. The only parameter that requires attention relates to the prevention of condensate dripping. This conclusion was also the outcome of Pavell and Hughes (9)
3.從觀點(diǎn)2、4、6和7，我得出結(jié)論，物品在滅菌器中的位置對(duì)于實(shí)現(xiàn)相同程度的滅菌沒(méi)有影響。唯一需要關(guān)注的參數(shù)是防止凝結(jié)水滴落。這也是Pavell和Hughes研究的結(jié)論。
4、空氣去除和蒸汽滲透
Air Removal and Steam Penetration
Steam sterilization is based on the use of pure steam. When air or other noncondensable gases (NCGs) are present, they will affect the sterilization on several levels
蒸汽滅菌基于使用純蒸汽。當(dāng)存在空氣或其他不可冷凝氣體（NCGs）時(shí)，它們會(huì)在多個(gè)層面上影響滅菌效果
1. Steam will follow the physical properties described above only when it is pure. When it is impure, the outcome is not predicted as easily.
1.只有純蒸汽才會(huì)遵循上述描述的物理屬性。當(dāng)它不純凈時(shí)，結(jié)果不容易預(yù)測(cè)
2. Effective steam sterilization is predicated on the steam being in contact with the item. NCGs create isolation and can limit the destructive effectiveness
of steam.
2.有效的蒸汽滅菌基于蒸汽與物品的接觸。不可冷凝氣體（NCGs）會(huì)造成隔離，可能限制蒸汽的破壞性效果。
3. Steam lethality is attributed to the presence of water molecules. NCGs reduce steam lethality because they do not include water molecules.
3.蒸汽的致命性歸因于水分子的存在。不可冷凝氣體降低了蒸汽的致命性，因?yàn)樗鼈儾话肿印?/span>
Steam purity is influenced by how steam is produced and transferred and by efficient air removal from the chamber and load. Assuming that steam is tested on a regular basis for low levels of NCGs2, proper air removal should be ensured before starting the sterilization phase. In most cases, air removal is more important than additional sterilization time and increased temperature. The PNSU calculations in the first section are valid only with efficient air removal so that the full lethality of steam is applied.
蒸汽的純度受其產(chǎn)生和轉(zhuǎn)移的方式以及從腔室和負(fù)載中有效去除空氣的影響。假設(shè)蒸汽會(huì)定期檢測(cè)低水平的不可冷凝氣體(NCGs)，那么在開始滅菌階段之前應(yīng)確保適當(dāng)?shù)目諝馊コＴ诖蠖鄶?shù)情況下，空氣去除比增加滅菌時(shí)間和提高溫度更為重要。第一部分中的PNSU計(jì)算僅在有效去除空氣的情況下才有效，以便發(fā)揮蒸汽的全部致命性。
Air removal and steam penetration are complementary, because the same channel that allows air to be removed from internal voids allows steam to enter these voids.
空氣去除和蒸汽滲透是相輔相成的，因?yàn)樵试S空氣從內(nèi)部空隙中排出的相同通道也允許蒸汽進(jìn)入這些空隙。
The level at which air is not considered to be harmful depends on the load. Small air bubbles that are dissolved in steam are not a problem, but their accumulation in closed packs or pockets can become an issue(16).
空氣無(wú)害的水平取決于負(fù)載。溶解在蒸汽中的小氣泡不是問(wèn)題，但如果它們?cè)诜忾]的包裝或口袋里積聚，可能會(huì)成為問(wèn)題。
Effective air removal and steam penetration are achieved by the repeated evacuation and entrance of steam into the voids. Collectively, this process entails dilution of the air in steam and subsequent extrusion of the mixture. The efficacy of the process is dictated by two factors:
通過(guò)反復(fù)抽出和進(jìn)入蒸汽到空隙中實(shí)現(xiàn)有效的空氣去除和蒸汽滲透?？偟膩?lái)說(shuō)，這個(gè)過(guò)程包括蒸汽中空氣的稀釋及其后混合物的擠出。這個(gè)過(guò)程的效果由兩個(gè)因素決定：
1.Values of pressure for the vacuum and steam pulses
1.真空和蒸汽脈沖的壓力值。
2. Pulse time. Slow pulses are more effective in removing air from challenging items, such as long lumens, porous loads, and packed items, because physical restrictions slow the evacuation and steam penetration. This property is the chief reason that a minimal load is required in an overkill cycle. In minimal loads, the evacuation time and steam pulse are shorter, impeding the air removal from and steam penetration of challenging items. In certain autoclaves, pulses duration can be set and be equal, regardless of load size, but in many autoclaves, this option does not exist. In such cases, this issue can be overcome through redundancy by adding more pulses or increasing the difference between the vacuum and steam pressures, rendering even shorter pulses sufficiently effective.
2.脈沖時(shí)間。慢速脈沖在去除具有挑戰(zhàn)性的物品中的空氣方面更有效，例如長(zhǎng)通道、多孔負(fù)載和包裝緊密的物品，因?yàn)槲锢硐拗茰p慢了抽氣和蒸汽滲透的速度。這種特性是過(guò)度殺菌周期中需要最小負(fù)載的主要原因。在最小負(fù)載中，抽氣時(shí)間和蒸汽脈沖時(shí)間較短，阻礙了從具有挑戰(zhàn)性的物品中去除空氣和蒸汽的滲透。在某些滅菌器中，可以設(shè)置脈沖持續(xù)時(shí)間并使其相等，不管負(fù)載大小如何，但在許多滅菌器中，并不提供這種選項(xiàng)。在這種情況下，可以通過(guò)增加脈沖次數(shù)或增加真空和蒸汽壓力之間的差異來(lái)實(shí)現(xiàn)冗余，使即使是更短的脈沖也足夠有效。
In an overkill cycle, air removal is the main parameter when determining whether an item is simple or difficult to sterilize. When air removal is conducted properly, steam will penetrate all voids, eliminating “hard-tosterilize or challenging items.” Item Preparation, Wrapping, and Orientation Preparation, wrapping, and orientation are significant factors in the success of the sterilization cycle, because they impact air removal, steam penetration, and condensate removal (8). An item that is validated after being prepared, wrapped, and oriented in the chamber according to specific instructions should always be sterilized in the manner that it was validated. For example, a tube coiling of a specific length should be inserted into a double bag and placed flat on the autoclave shelf. A validated item includes its preparation, wrapping, and orientation.
在過(guò)度殺菌周期中，空氣去除是決定物品是簡(jiǎn)單還是難以滅菌的主要參數(shù)。當(dāng)空氣去除進(jìn)行得當(dāng)，蒸汽將滲透到所有空隙中，消除了“難以滅菌或具有挑戰(zhàn)性的物品”。物品的準(zhǔn)備、包裝和方向 準(zhǔn)備、包裝和方向是滅菌周期成功的重要因素，因?yàn)樗鼈冇绊懣諝獾娜コ?、蒸汽的滲透和凝結(jié)水的排出。根據(jù)特定說(shuō)明在腔室中準(zhǔn)備好、包裝好并定位好的物品應(yīng)該始終按照其經(jīng)過(guò)驗(yàn)證的方式進(jìn)行滅菌。例如，特定長(zhǎng)度的管圈應(yīng)插入雙層袋中，并平放在滅菌器架上。經(jīng)過(guò)驗(yàn)證的物品包括其準(zhǔn)備、包裝和方向。
Data Collection and Interpretation Data were collected from actual validation runs that were performed at a specific facility from 2017 to 2019, as presented in Table III. The data are used to assess differences between maximal and minimal load results.
數(shù)據(jù)收集與解釋：數(shù)據(jù)收集自2017年至2019年在特定設(shè)施進(jìn)行的實(shí)際驗(yàn)證運(yùn)行，如表III所示。這些數(shù)據(jù)被用來(lái)評(píng)估最大裝載量和最小裝載量結(jié)果之間的差異
The maximal load is prepared by collecting the more challenging items (items with a minimal F0 value) from all validated loadings.
最大裝載量是通過(guò)從所有經(jīng)過(guò)驗(yàn)證的裝載中收集更具挑戰(zhàn)性的物品（即具有最小F0值的物品）來(lái)準(zhǔn)備的。
The minimal load usually includes one item that is found to be more challenging during the run of the maximal load
最小裝載量通常包括在最大裝載量運(yùn)行過(guò)程中發(fā)現(xiàn)的更具挑戰(zhàn)性的一個(gè)物品。
Data were collected from 數(shù)據(jù)收集自：
6 autoclaves, varying in size and age
6臺(tái)不同尺寸和使用年限的高壓蒸汽滅菌器
4 types of loads—garments, gloves, tools, and rubber stoppers
4種不同類型的裝載物品：服裝、手套、工具和橡膠塞
4 types of air removal processes
4種不同的空氣去除過(guò)程
Cycles from 2017, 2018, and 2019
2017年、2018年和2019年的循環(huán)數(shù)據(jù)
5、從收集的數(shù)據(jù)里得到以下幾點(diǎn)看法
There are several insights from the data collection
1. Minimal load F0 values were within the values that were obtained in the maximal load (the highest and lowest F0 values were found in the maximal load cycles) (Figure 4). These data indicate that faster air removal and faster heating, which characterize the minimal cycle, do not necessarily provide the lowest lethality values.
1.最小裝載量的F0值在最大裝載量周期內(nèi)獲得的值范圍內(nèi)（最大和最小的F0值出現(xiàn)在最大裝載量周期中）。這些數(shù)據(jù)表明，最小周期特征的更快的空氣去除和更快的加熱，并不一定提供最低的致命性值。
2. In certain cases, the differences in F0 values between the hottest and coldest points in a specific cycle might appear to be significant, but when CT values are considered, the differences are small .
2.在特定周期中，最熱點(diǎn)和最冷點(diǎn)之間的F0值差異可能看起來(lái)很顯著，但當(dāng)考慮到CT值時(shí)，這些差異很小。
3. Because the thermocouples that are used for the PQ study are calibrated to ±0.5?C, some differences can be related to calibration tolerances; when this factor is considered, the results indicate excellent temperature uniformity inside all of the loads.
3.由于用于PQ研究的熱電偶校準(zhǔn)精度為±0.5?C，一些差異可能與校準(zhǔn)容差有關(guān)；當(dāng)考慮到這個(gè)因素時(shí)，結(jié)果表明所有裝載內(nèi)部的溫度均勻性都很好
4. The correlation was low (0.26) between the equilibration time and correlated temperature differences. It would be expected that a short equilibration time indicates faster heating of the items, thus reducing temperature differences, but the low correlation does not support this relationship. Pavell and Hughes (9) also observed this finding. It would be interesting to understand the reason, scientifically. Practically speaking, the lack of correlation has no effect on the overall conclusions that are related to the overkill cycle
4.平衡時(shí)間與相關(guān)溫度差異之間的相關(guān)性很低（0.26）。人們可能會(huì)預(yù)期，較短的平衡時(shí)間表明物品加熱更快，從而減少溫度差異，但低相關(guān)性并不支持這種關(guān)系。Pavell和Hughes（9）也觀察到了這一發(fā)現(xiàn)。從科學(xué)上理解這一原因?qū)⑹怯腥さ?。?shí)際上，缺乏相關(guān)性對(duì)與過(guò)度殺菌周期相關(guān)的總體結(jié)論沒(méi)有影響。
The results of the data collection and analysis show clearly that the differences in lethality between loads and between items in the load are small. The large differences in the mass or density of arrangement of the items between the maximal and minimal loads did not have any effect or direction that was related to the lethality that was gained by the items.
數(shù)據(jù)分析和收集的結(jié)果清楚地表明，裝載量之間以及裝載量?jī)?nèi)物品之間的致命性差異很小。在最大裝載量和最小裝載量之間，物品的質(zhì)量或排列密度的大差異并沒(méi)有對(duì)物品獲得的致命性產(chǎn)生任何相關(guān)的影響或趨勢(shì)。
When evaluating the results for an overkill cycle, the differences are negligible. No item can be considered “hard to sterilize” or “challenging”, because all items achieved lethality values far beyond the initial requirements of the overkill cycle (F0 ≥ 15 min, which also covers the EU requirements) and the sterility assurance level that was required.
在評(píng)估過(guò)度殺菌周期的結(jié)果時(shí)，差異是可以忽略不計(jì)的。沒(méi)有任何物品可以被視為“難以滅菌”或“具有挑戰(zhàn)性”，因?yàn)樗形锲返闹旅灾刀歼h(yuǎn)遠(yuǎn)超過(guò)了過(guò)度殺菌周期的初始要求（F0 ≥ 15分鐘，這也符合歐盟的要求）以及所需的無(wú)菌保證水平。
6、結(jié) 論
Conclusions
Overkill cycles, as currently used in industry, are excessive, attaching overly conservative safeguards to safeguards. The approach of allowing flexible loads for validated items, if implemented with the principles following, will result in safe and effective sterilization cycles at far lower cost to industry and the environment.
過(guò)度殺菌周期，按照目前工業(yè)中的使用方式，是過(guò)度的，它在保護(hù)措施上增加了過(guò)于保守的防護(hù)措施。如果按照以下原則實(shí)施允許已驗(yàn)證物品的靈活裝載的方法，將能夠在大幅降低工業(yè)和環(huán)境成本的同時(shí)，實(shí)現(xiàn)安全有效的滅菌周期
The overkill cycle provides safe and robust sterilization for any load configuration if certain simple and basic principles are always followed:
過(guò)度殺菌周期，如果始終遵循一些簡(jiǎn)單和基本原則，可以為任何裝載配置提供安全和可靠的滅菌
1. The cycle should be an extended overkill cycle. To allow load flexibility, more robust overkill cycles, with a calculated F0 value >25 minutes, are recommended to ensure the destruction of Geobacillus stearothermophilus BIs.
1.周期應(yīng)為擴(kuò)展的過(guò)度殺菌周期：為允許裝載靈活性，推薦使用計(jì)算出的F0值大于25分鐘的更強(qiáng)大的過(guò)度殺菌周期，以確保能夠破壞嗜熱脂肪芽孢桿菌（Geobacillus stearothermophilus）生物指示劑（BIs）
2. A validated item is one that has been validated by three penetration cycles (using thermocouples and BIs that are inserted into adjacent locations inside of the item) in any loading pattern. The term “item” includes the specific wrapping that is used when validated.
2.驗(yàn)證物品：經(jīng)過(guò)驗(yàn)證的物品是指在任何裝載模式下，通過(guò)三次穿透周期（使用插入物品內(nèi)部相鄰位置的熱電偶和生物指示劑）進(jìn)行驗(yàn)證的物品。“物品”一詞包括在驗(yàn)證時(shí)使用的具體包裝方式
3. The item must be placed in the same orientation in which it was validated and in a manner that will not block air or steam passage to other items.
3.物品的放置：物品必須以其驗(yàn)證時(shí)相同的方向放置，并且不得阻礙空氣或蒸汽流向其他物品。
4. Due to greater condensation from heavy metal items, they should be placed on the lower shelves to avoid dripping onto another item
4.重物的放置：由于重金屬材料會(huì)產(chǎn)生更多的凝結(jié)水，應(yīng)將它們放置在較低的架子上，以避免水滴落到其他物品上。
5. The air removal stage should be designed to provide redundancy, such that even with fast pulses, it will be efficient. (If the autoclave is capable of controlling the timing of the pulses to be equal for maximal and minimal loads, the minimal load cycle validation is no longer relevant, and it could be skipped or be performed only once to ease regulatory questions [19]).
5.空氣去除階段的設(shè)計(jì)：應(yīng)設(shè)計(jì)具有冗余性的空氣去除階段，以便即使在快速脈沖的情況下也能保持高效率。如果滅菌器能夠控制脈沖時(shí)間，使最大和最小負(fù)載的脈沖時(shí)間相等，那么最小負(fù)載周期驗(yàn)證就不再相關(guān)了，可以省略或僅執(zhí)行一次以便于監(jiān)管問(wèn)題的解答。
6. Revised or new loads are created under a change control procedure or a detailed SOP that includes full documentation and pictures of the revised or new load
6.新裝載或修訂裝載的創(chuàng)建：新裝載或修訂裝載應(yīng)在變更控制程序或詳細(xì)標(biāo)準(zhǔn)操作程序(SOP)下創(chuàng)建，包括完整的文檔記錄和修訂或新裝載的圖片。
7、總體結(jié)論可以總結(jié)如下
The overall conclusion can be summarized as follows
If the preceding principles are followed, an item that has been validated in a specific overkill cycle will be effectively sterilized in any other load configuration using the same sterilization cycle parameters (including the air removal phase parameters), wrapping, and orientation. No additional validation is required to ensure that the combination of such items will be sterilized properly.
如果遵循前述原則，那么在一個(gè)特定的過(guò)度殺菌周期中經(jīng)過(guò)驗(yàn)證的物品將在任何其他使用相同滅菌周期參數(shù)（包括空氣去除階段參數(shù)）、包裝和方向的裝載配置中被有效滅菌。為了確保這些物品的組合能夠被正確滅菌，不需要額外的驗(yàn)證。（這意味著，一旦物品在特定的過(guò)度殺菌周期中被驗(yàn)證，就可以在不同的裝載條件下信任其滅菌效果，而無(wú)需為每種新的裝載配置重復(fù)驗(yàn)證過(guò)程。這為滅菌過(guò)程提供了靈活性和效率，同時(shí)保持了所需的無(wú)菌保證水平。）
Consequently, several options are created when applying the preceding principles, such as the following:
應(yīng)用前述原則后，會(huì)創(chuàng)建幾種選擇，例如：
1. A new item can be tested alone, running 3 penetration cycles, after which it can be multiply or combined with any other validated item.
1.單獨(dú)測(cè)試新物品：新物品可以單獨(dú)進(jìn)行測(cè)試，運(yùn)行3次穿透周期，之后它可以被多次使用或與其他經(jīng)過(guò)驗(yàn)證的物品組合。
2. A combination of any validated item in any number is allowed
2.任何數(shù)量的經(jīng)過(guò)驗(yàn)證的物品組合：允許將任何數(shù)量的經(jīng)過(guò)驗(yàn)證的物品組合在一起。
The two options are demonstrated in Figure 6. Allowing facilities to use the preceding approach will provide flexibility in their operation and can significantly reduce the validation workload without any adverse impact on patient safety
圖6展示了兩種選項(xiàng)。允許設(shè)施采用前述方法將為其運(yùn)營(yíng)提供靈活性，并且可以在不犧牲患者安全的前提下顯著減少驗(yàn)證工作量。這種方法有助于提高滅菌過(guò)程的效率，同時(shí)確保滅菌效果滿足安全標(biāo)準(zhǔn)。
來(lái)源：GMP的那些事
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