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近日，ISPE博客發(fā)布了《去熱原隧道驗證》的文章，文中對去熱原隧道的設(shè)計、壓差、驗證測試以及驗證項目失敗的原因進行了詳細的闡述，翻譯如下：
INTRODUCTION
介紹
Dry-heat depyrogenation is the primary method for the inactivation of bacterial endotoxin through thermal destruction, and it is commonly used with heat-resistant materials, such as glassware.³? The critical process parameters in a dry-heat depyrogenation process are time and temperature.²
干熱除熱原法是通過熱破壞滅活細菌內(nèi)毒素的主要方法，通常適用于玻璃器皿等耐熱材料。 干熱除熱原工藝中的關(guān)鍵工藝參數(shù)是時間和溫度。
The production of parenteral products requires products to be sterile as well as to be free of pyrogens.¹ Endotoxin is the most significant pyrogen in the health care industry.? These are high-molecular weight complexes associated with the outer membrane of gram negative bacteria.? A depyrogenation tunnel is typically used for the inactivation of pyrogens prior to aseptic filling of glass containers, and comes after the washing step. This type of tunnel provides an automated continuous depyrogenation process and usually consists of three zones: a pre-heating zone to pre-warm the glass containers; a hot zone, where the containers are exposed to the required temperature the sufficient time to achieve the depyrogenation effect expected; and a cooling zone, where the containers are returned to room temperature prior to leaving the tunnel and entering the filling environment.³ The exposure time of the load inside the tunnel is a function of the length of the tunnel, temperature and the speed of the conveyor belt. The qualification of a depyrogenation process in a tunnel involves the equipment qualification (Installation qualification, or IQ, and the operational qualification, or OQ) and the depyrogenation process qualification (PQ).?
注射劑產(chǎn)品的生產(chǎn)要求產(chǎn)品既無菌又無熱原。 內(nèi)毒素是醫(yī)療行業(yè)中最重要的熱原。 它們是與革蘭氏陰性菌外膜相關(guān)的高分子量復(fù)合物。 除熱原隧道通常用于玻璃容器無菌灌裝前的熱原滅活，位于清洗工序之后。這類隧道可實現(xiàn)自動化連續(xù)除熱原工藝，通常包含三個區(qū)域：預(yù)熱區(qū)，用于預(yù)熱玻璃容器；高溫區(qū)，容器在此處暴露于所需溫度足夠時長，以達到預(yù)期的除熱原效果；冷卻區(qū)，容器在離開隧道進入灌裝環(huán)境前，在此處恢復(fù)至室溫。 負載在隧道內(nèi)的暴露時間由隧道長度、溫度和網(wǎng)帶速度決定。隧道中除熱原工藝的確認包括設(shè)備確認（安裝確認，即IQ；運行確認，即OQ）和除熱原工藝確認（PQ）。
A validation lifecycle approach is recommended to develop a thorough understanding of the equipment and process by investing more time on the process design phase, prior to validation, and then by the continued monitoring of the process after validation to ensure that the process is delivering the expected quality while confirming the state of control of the process.?·? This paper utilizes the lifecycle approach and focuses on the first two stages: Process Design and Process Qualification to provide recommendations for a standardized and science-based approach for the qualification of a depyrogenation tunnel.
建議采用驗證生命周期方法，在驗證前將更多時間投入工藝設(shè)計階段，以深入理解設(shè)備和工藝；驗證后持續(xù)監(jiān)控工藝，確保工藝能產(chǎn)出預(yù)期質(zhì)量的產(chǎn)品，同時確認工藝的受控狀態(tài)。 本文采用生命周期方法，聚焦前兩個階段：工藝設(shè)計與工藝確認，為除熱原隧道的確認提供標準化、基于科學(xué)的方法建議。
LIFECYCLE APPROACH TO A DEPYROGENTATION PROCESS VALIDATION FOR A DEPYROGENATION TUNNEL
除熱原隧道除熱原工藝驗證的生命周期方法
The lifecycle approach to validation is recommended in the 2011 US Food and Drug Administration guidance document, titled “Process Validation: General Principles and Practices,” where it states that “the lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.”? According to the lifecycle approach, the validation can be divided into three stages:
2011年FDA題為《工藝驗證：一般原則與實踐》的指導(dǎo)文件中推薦了驗證的生命周期方法，其中指出“生命周期概念將產(chǎn)品與工藝開發(fā)、商業(yè)化生產(chǎn)工藝的確認，以及常規(guī)商業(yè)化生產(chǎn)期間工藝受控狀態(tài)的維持關(guān)聯(lián)起來。”根據(jù)生命周期方法，驗證可分為三個階段：
Stage One: Process design
第一階段：工藝設(shè)計
Stage Two: Process Qualification
第二階段：工藝確認
Stage Three: Continued process verification
第三階段：持續(xù)工藝確認
Some of the main deliverables of Stage One include the development of the user requirement specification (URS), the definition of the critical quality attributes (CQAs) and critical process parameters (CPPs), the development of the depyrogenation process and the creation of the standard operating procedure (SOP). During Stage Two, the equipment qualification is completed with the performance of the IQ and OQ and the depyrogenation process is qualified during the performance qualification (PQ) according to the approved protocols. During Stage Three, the process is continuously monitored to confirm the expected results and the state of control of the process.
第一階段的主要交付成果包括用戶需求規(guī)范（URS）的制定、關(guān)鍵質(zhì)量屬性（CQAs）與關(guān)鍵工藝參數(shù)（CPPs）的定義、除熱原工藝的開發(fā)，以及標準操作規(guī)程（SOP）的編制。在第二階段，通過執(zhí)行IQ和OQ完成設(shè)備確認，并根據(jù)批準的方案，在性能確認（PQ）期間完成除熱原工藝的確認。在第三階段，持續(xù)監(jiān)控工藝，以確認預(yù)期結(jié)果及工藝的受控狀態(tài)。
This concept paper will concentrate on the main points of the Process Design phase and the Process Qualification phase.
本概念文件將聚焦于工藝設(shè)計階段與工藝確認階段的核心要點。
DEPYROGENATION PROCESS DESIGN
除熱原工藝設(shè)計
During the Process Design phase, the specifications of the depyrogenation tunnel are defined in the URS. Operational specifications include the capacity of the tunnel in containers/hour according to production requirements, specific load size (e.g., volume and dimensions of glassware containers), temperature range and conveyor belt speed.
在工藝設(shè)計階段，除熱原隧道的規(guī)格在URS中明確。操作規(guī)格包括根據(jù)生產(chǎn)需求確定的隧道容量（單位：容器/小時）、特定負載尺寸（例如玻璃容器的容積和尺寸）、溫度范圍及網(wǎng)帶速度。
As for the critical process parameters (CPPs), these are time and temperature for a dry-heat depyrogenation process. The process is driven by a conveyor belt through each of the three zones. In the hot zone, dry air is heated to the specified temperatures through heat exchangers in order to heat the containers. The exposure time of the load inside the tunnel is a function of the length of the tunnel, the temperature and the speed of the conveyor belt.
對于關(guān)鍵工藝參數(shù)（CPPs）而言，干熱除熱原工藝的關(guān)鍵參數(shù)是時間和溫度。工藝由網(wǎng)帶驅(qū)動，使負載依次通過三個區(qū)域。在高溫區(qū)，干空氣通過熱交換器加熱至規(guī)定溫度，以對容器進行加熱。負載在隧道內(nèi)的暴露時間由隧道長度、溫度和網(wǎng)帶速度決定。
The process operational parameters of a depyrogenation tunnel should be designed to achieve at least a three-log reduction of bacterial endotoxin.³·? The temperature of the hot zone in depyrogenation tunnels is usually set between 220°C and 350°C.¹ It is important that all the different vials which are going to be depyrogenated are exposed to at least the defined temperature and for not less than the time determined in the design phase. The European Pharmacopoeia Chapter 2.6.8. establishes dry heat at a minimum of 250°C for at least 30 minutes for depyrogenation of materials such as glassware. For higher temperatures the depyrogenation time required might be only a few minutes.
除熱原隧道的工藝操作參數(shù)應(yīng)設(shè)計為至少實現(xiàn)細菌內(nèi)毒素的3個對數(shù)級降低。 除熱原隧道高溫區(qū)的溫度通常設(shè)置在220°C至350°C之間。重要的是，所有待除熱原的不同規(guī)格西林瓶都應(yīng)暴露于至少規(guī)定的溫度下，且暴露時長不短于設(shè)計階段確定的時間?！稓W洲藥典》第2.6.8章規(guī)定，對于玻璃器皿等材料的除熱原，干熱條件為至少250°C、持續(xù)至少30分鐘。若溫度更高，所需的除熱原時間可能僅為幾分鐘。
Similar to the F0 value for steam sterilization, Fh is a measure of heat input and is used to calculate the time in minutes equivalent to a lethality or endotoxin destruction effect delivered by dry heat at 250°C. For depyrogenation the minimum z-value is set at 46.5°C. Although there is no minimum Fh value required for depyrogenation, the determination of the Fh value for each probe may be helpful to ensure consistency and reproducibility of the depyrogenation process.²
與蒸汽滅菌的F0值類似，F(xiàn)h是熱量輸入的量度，用于計算相當(dāng)于250°C干熱所產(chǎn)生的致死或內(nèi)毒素破壞效果的分鐘數(shù)。對于除熱原，最小Z值設(shè)定為46.5°C。盡管除熱原沒有要求的最小Fh值，但確定每個探頭的Fh值可能有助于確保除熱原工藝的一致性和重現(xiàn)性。
Particle count in the depyrogenation tunnel should be appropriate to the exiting environment classification.? Operational qualification should verify that the HEPA-filtered aseptic environment is maintained within the specifications for an ISO 5/Grade A environment.³ Unidirectional air flow is required to ensure that clean air is always supplied for the heating of the containers. The pressure difference between the zones of the tunnel is needed to avoid air moving from dirty to clean.? The minimum differential pressure depends on the design of the tunnel and therefore the specification should be checked with the manufacturer.³·?
除熱原隧道內(nèi)的粒子計數(shù)應(yīng)與出口環(huán)境潔凈等級相匹配。OQ應(yīng)驗證經(jīng)HEPA過濾的無菌環(huán)境符合ISO 5/A級環(huán)境要求。 需要單向氣流以確保始終為容器加熱供應(yīng)潔凈空氣。隧道各區(qū)域之間的壓差是為了避免空氣從臟區(qū)流向潔凈區(qū)。最小壓差取決于隧道的設(shè)計，因此應(yīng)與制造商確認該規(guī)格要求。
Figure 1: Scheme of the pressure cascade in a depyrogenation tunnel. The image is courtesy of Syntegon.
圖1：除熱原隧道內(nèi)的壓力梯度示意圖。該圖片由Syntegon提供。
Empty and loaded chamber temperature studies can be performed as part of the factory acceptance test (FAT) and then repeated after equipment installation and commissioning at the manufacturing facility, as part of the site acceptance test (SAT) and/or as part of the IQ/OQ. Empty chamber temperature distribution studies are necessary to confirm that the air balance of the heated air supply will provide even heating. For these studies thermocouples are placed inside the tunnel equally distributed. The variability in the temperature in the different areas of the tunnel depends on the design and expected variability may therefore be derived from manufacturer’s specifications. Loaded chamber heat distribution studies are also performed to assess the impact of the load in the heat distribution uniformity of the hot zone in the tunnel.²
空載與滿載溫度測試可作為工廠驗收測試（FAT）的一部分開展，隨后在生產(chǎn)設(shè)施完成設(shè)備安裝與調(diào)試后，作為現(xiàn)場驗收測試（SAT）和/或安裝確認/運行確認（IQ/OQ）的一部分重復(fù)進行。空載溫度分布測試是必要的，用于確認熱空氣供應(yīng)的氣流平衡可實現(xiàn)均勻加熱。此類測試中，熱電偶會均勻分布在隧道內(nèi)部。隧道不同區(qū)域的溫度波動取決于設(shè)計，預(yù)期波動可參考制造商的規(guī)格說明。滿載熱分布測試也會開展，用于評估負載對隧道高溫區(qū)熱分布均勻性的影響。
Heat distribution inside the load can vary depending on the load mass, configuration and other parameters.² For this reason, heat penetration studies are done to help determine “worst-case” conditions in the load and cold spots. Heat penetration studies confirm the temperature of the load under operating conditions reaches and maintains depyrogenation temperatures. Worst-case operating conditions (e.g., increased belt speed and lower temperature set point) are used for these studies. Heat penetration studies can be done concurrent with loaded temperature distribution studies.³
負載內(nèi)部的熱分布會因負載質(zhì)量、構(gòu)型及其他參數(shù)而變化。因此，需開展熱穿透測試，以幫助確定負載中的“最差情況”條件與冷點。熱穿透測試用于確認運行條件下負載的溫度能達到并維持除熱原溫度。此類測試采用最差情況運行條件（例如，較高的網(wǎng)帶速度、較低的溫度設(shè)定點）。熱穿透測試可與滿載溫度分布測試同時開展。
The “depyrogenation dwell time” is the period during which the containers remain in the hot zone of the tunnel. The dwell time can be derived based on empty and loaded chamber studies.³
“除熱原停留時間”是容器停留在隧道高溫區(qū)的時長。該停留時間可基于空載與滿載測試得出。
After the containers have gone through the hot zone for the duration needed for the depyrogenation, they are cooled down to room temperature in the cool zone prior to the aseptic filling. In order to mitigate any risk of microbial contamination of the containers passing through this zone, it is recommended that the environment is sterilized prior to each filling campaign. This sterilization process is generally by dry-heat and should be validated to reach at least a six-log reduction of bacterial spores. For the validation, dry-heat-resistant bacterial spores should be used as biological indicators, such as B. atrophaeus spores.³
容器在高溫區(qū)完成除熱原所需時長后，會在冷卻區(qū)冷卻至室溫，再進入無菌灌裝環(huán)節(jié)。為降低容器通過該區(qū)域時的微生物污染風(fēng)險，建議在每個灌裝批次前對該環(huán)境進行滅菌。該滅菌過程通常采用干熱法，且需驗證其能實現(xiàn)至少6個對數(shù)級的細菌孢子降低。驗證時，應(yīng)使用耐熱細菌孢子作為生物指示劑，例如萎縮芽孢桿菌孢子。
DEPYROGENATION PROCESS QUALIFICATION
除熱原工藝確認
During Stage Two or Process Qualification phase, the depyrogenation process as designed in the previous phase is qualified. The equipment qualification is completed with the realization of the IQ and OQ and the depyrogenation process is qualified during the PQ according to the approved protocols. During the PQ of a depyrogenation tunnel endotoxin reduction challenge studies are performed and should confirm that the tunnel under production operating conditions is able to achieve a minimum 3-log reduction of bacterial endotoxin. These studies typically involve inoculating bacterial endotoxin, e.g. 5000 EU of endotoxin units in the containers to be depyrogenated and verifying after the reduction after exposing the components to the designed conditions with the depyrogenation tunnel. The disposition of the components in the tunnel should be representative of production conditions. An overkill approach can be used and consists of verifying greater than a three-log endotoxin reduction under worst-case conditions, which might include an increased belt speed and lower temperature set point. Endotoxin spiking method and recovery should be designed and determined prior to challenges studies. Recovery studies should be performed with a carrier of the same material as the ones to be depyrogenated in the tunnel.³
在第二階段（即工藝確認階段），需對前一階段設(shè)計的除熱原工藝進行確認。通過完成安裝確認（IQ）與運行確認（OQ），設(shè)備確認即告完成；而除熱原工藝則需根據(jù)批準的方案，在性能確認（PQ）期間完成確認。在除熱原隧道的PQ階段，需開展內(nèi)毒素降低挑戰(zhàn)測試，以確認隧道在生產(chǎn)運行條件下能實現(xiàn)細菌內(nèi)毒素降低至少3個對數(shù)級。此類測試通常包括：在待除熱原的容器中接種細菌內(nèi)毒素（例如5000內(nèi)毒素單位），并將容器置于除熱原隧道的設(shè)計條件下處理后，驗證內(nèi)毒素的降低效果。容器在隧道內(nèi)的擺放方式應(yīng)能代表生產(chǎn)條件?？刹捎眠^度殺滅法，即在最差情況條件（可能包括較高的網(wǎng)帶速度、較低的溫度設(shè)定點）下，驗證內(nèi)毒素降低幅度超過3個對數(shù)級。內(nèi)毒素加標方法與回收需在挑戰(zhàn)測試前設(shè)計并確定?；厥諟y試應(yīng)使用與隧道中待除熱原容器材質(zhì)相同的載體開展。
Table 1 summarizes the main points during depyrogenation process design and qualification and the potential root causes when failure occurs.
表1總結(jié)了除熱原工藝設(shè)計與確認過程中的要點，以及出現(xiàn)失敗時的潛在根本原因。
TABLE 1: POINTS TO CONSIDER FOR THE QUALIFICATION OF A DEPYROGENATION TUNNEL
表1：除熱原隧道確認需考慮的要點
來源：Internet
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