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嘉峪檢測網 2024-08-15 18:54
Clarity in GMP Guidance Pharmaceutical lsolator Leak Integrity Classes and Leak Rates
GMP指南中藥品隔離器泄漏完整性等級和泄漏率的明確性
Background to development of PHSS Guidance on Barrier Isolator technology Leak integrity classes and leak rates/ acceptance criteria for qualification and routine monitoring.
PHSS關于屏障隔離技術指導文件的背景是開發泄漏完整性等級和泄漏率/驗收標準，用于資格認證和常規監測。
Complex pharmaceutical isolator systems cannot comply with the requirements set out in the older generic Standard ISO 10648-2 that defines four leak integrity classes
復雜藥品隔離系統無法符合舊版通用標準ISO 10648-2的要求，該標準定義了四個泄漏完整性等級
In the ISO standard the highest class 1 at 0.05% volume/hour leak rates typically applies to rigid nuclear glove boxes or inert atmosphere glove boxes used for oxygen and moisture sensitive material processing that can be tested at high pressures and over long test periods e.g. over 1000 pascal test pressures with up to one hour test periods (with result adjustments for variations of temperature and atmospheric pressure through the test period). Such high integrity, extended test periods and relatively high test pressures are not practical to apply to complex pharmaceutical isolators e.g. filling lines
在ISO標準中，最高等級1的0.05%/小時的泄漏率通常適用于剛性核手套箱或惰性氣氛手套箱，這些手套箱用于對氧氣和水分敏感的材料處理，可以在高壓下進行測試，并在長時間測試期間（例如超過1000帕斯卡的測試壓力，測試時間長達一小時，并且根據測試期間溫度和大氣壓力的變化進行結果調整）。這種高完整性、延長的測試周期和相對較高的測試壓力對于復雜的藥品隔離器（例如灌裝線）來說是不切實際的。
The ISO Class 2 leak integrity at 0.25% vol/h typically applies to small flexible film isolators and containment isolators and requires relatively high test pressures and extended test periods (in range of 30 minutes). Integrity testing at this level of integrity and extended test time is also not considered practical for production scale pharmaceutical isolators
ISO 2級泄漏完整性0.25%/小時通常適用于小型柔性薄膜隔離器和密閉隔離器，需要相對較高的測試壓力和延長的測試周期（大約30分鐘）。在這種完整性水平和延長的測試時間內進行完整性測試，對于生產規模的藥品隔離器來說也不實用。
The ISO Class 3 leak integrity at 1% vol/h can applied to small scale pharmaceutical isolators in comparison to small laboratory/ containment Isolators the ISO10648- 2 standard was mainly drafted around. However as a whole the ISO standard is considered impractical to apply to the full range of Pharmaceutical isolators including larger scale filling Isolator systems that include complex sealing systems with
integrated process machinery. Such complex Filling isolators were not fully developed when this ISO standard was written hence not considered in drafting.
ISO 3級泄漏完整性1%/小時可以應用于小型藥品隔離器，與ISO10648-2標準主要起草時考慮的小型實驗室/密閉隔離器相比。然而，作為一個整體，ISO標準被認為不適用于包括具有復雜密封系統和集成工藝機械的大規模灌裝隔離器系統在內的全部藥品隔離器。這種復雜的灌裝隔離器在ISO標準起草時并未完全開發，因此在起草時未被考慮。
The lowest ISO class 4 leak integrity at 10% vol/h leak rate presents at leak rate that cannot be automated via a typically applied pressure decay method (instead requires a pressure hold method that is more suitable for duct work integrity testing) and would not safely contain a gaseous bio-decontamination agent to avoid operator exposure at the OEL. Such a high level of leakage is not considered acceptable for Pharmaceutical isolators.
最低的ISO 4級泄漏完整性在10% vol/h泄漏率下，其泄漏率不能通過通常應用的壓力衰減法自動化(而是需要更適合管道工作完整性測試的壓力保持法)，并且不能安全地包含氣態生物去污劑，以避免操作人員暴露在OEL。對于藥物隔離器來說，如此高的泄漏水平是不可接受的。
In a Pharmaceutical isolator barrier system for a filling line the complete system integrity combines leakage through the barrier and leakage through process machine bedplates. Typically a leak integrity of 1% vol/h is applied to the Machine ‘Bed plate’ alone that is subsequently integrated within a full barrier system.
在灌裝生產線的制藥隔離屏障系統中，完整的系統完整性結合了通過屏障和通過工藝機器床板的泄漏。通常，僅對機器“床板”施加1% vol/h的泄漏完整性，即隨后集成在一個完整的屏障系統中。
Within the PHSS leak integrity classes that defines a range from 1% to 5% vol/h an allowance is made to accommodate bed plate leakage in the overall integrity test. PHSS leak integrity classes apply to small laboratory scale pharmaceutical isolators without bed plate integrations but including barrier penetrations e.g. Rapid transfer ports, sterility test pumps through larger complex aseptic process filling isolators
在PHSS泄漏完整性等級中，定義了1%到5%/小時的范圍，允許在整體完整性測試中容納底板泄漏。PHSS泄漏完整性等級適用于沒有底板集成但包括屏障穿透的小規模實驗室藥品隔離器，例如快速轉移端口，無菌測試泵，通過更復雜的無菌工藝灌裝隔離器。
Aseptic-Containment may also be required in which case a higher leak integrity class may be specified to manage risks in containment of hazardous sterile products.
可能還需要無菌-密閉，這種情況下可能會指定更高泄漏完整性等級，以管理危險無菌產品的密閉風險。
The limit of 5% vol/h is considered as a maximum that can be applied to an integrity test using the automated pressure decay method without imposing high test pressures to allow for pressure decay without dropping below the operating pressure. Such a level of leak integrity is suitable for complex pharmaceutical isolators used for aseptic processing.
5%/小時的限制被認為是使用自動化壓力衰減方法進行完整性測試的最大值，而不會施加高壓以允許壓力衰減而不降至操作壓力以下。這種泄漏完整性水平適用于用于無菌工藝的復雜藥品隔離器。
Based on Cleanroom space HVAC/ Air handling dilution of any VHP/VH202 leakage calculations can demonstrate room VHP concentrations cannot reach OEL levels of 1ppm at 5% vol/h leakage.
基于潔凈室空間HVAC/空氣處理對任何VHP/VH202泄漏的稀釋，計算可以證明房間VHP濃度在5%/小時的泄漏下無法達到1ppm的OEL水平。
Implementing Pharmaceutical Isolator integrity testing.
實施藥品隔離器完整性測試
Pharmaceutical isolator leak integrity testing is typically applied at a test pressure of a minimum of 2X the isolator operating pressure allowing for the fact that after the allowable pressure decay the final test result should not be lower than the operating pressure.
藥品隔離器泄漏完整性測試通常在至少是隔離器操作壓力2倍的測試壓力下應用，允許在允許的壓力衰減之后，最終的測試結果不應低于操作壓力。
The short test periods significantly reduce the risk of false fail results from unexpected variations of temperature and barometric pressure during the test period. Leak integrity rates are based on stable test environment conditions as both temperature and atmospheric pressure fluctuations impact the pressure decay result e.g. a variation of
temperature in the tested volume of 1 degree centigrade correlates to approximately 350 pascal pressure variation and 0.07 degrees centigrade correlates to a pressure variation of approximately 25 pascal plus variation of atmospheric pressure of 1mbar
results in 100 pascal pressure variation during integrity testing. Such significant variation can take a significant portion of the acceptance criteria and can lead to a false fail result. Consideration should also be given to pressure differential change impact as operators enter cleanrooms with corresponding fluctuations as doors open and close.
短測試周期顯著降低了由于測試期間意外的溫度和氣壓變化而導致的誤判風險。泄漏率基于穩定的測試環境條件，因為溫度和大氣壓力波動都會影響壓力衰減結果。例如，測試體積中溫度變化1℃，大約對應于350Pa的壓力變化，而0.07℃的變化對應于大約25pa的壓力變化，加上大氣壓力1mbar的變化，結果是在完整性測試期間100帕斯卡的壓力變化。這種顯著的變化可能會占據驗收標準的重要部分，并可能導致誤判。還應考慮操作員進入潔凈室時壓力差變化的影響，以及門開啟和關閉時的相應波動。
Application of leak integrity testing should be considered before zone disinfection and after batch production (book ending production operations) to support any root cause investigation if EM later reports a contamination event.
應該考慮在區域消毒之前應用泄漏完整性測試，并在批量生產之后（生產操作結束）進行，以支持任何根本原因調查（如果EM報告污染事件）。
It is not possible to continuously monitor Isolator leak integrity and other strategies are required to monitor impact of isolator leak integrity loss during production operations e.g. environmental monitoring and physical changes in pressure differentials. Such process monitoring will have limitations in detection of leak integrity loss during production operations so it is important to trend leak integrity test results so this CPP; critical process parameter can be assessed in performance and risk assessed for impact as a result of deviation.
無法連續監測隔離器泄漏完整性，需要其他策略來監測生產操作期間隔離器泄漏完整性損失的影響，例如環境監測和壓差的身體變化。這種過程監測在檢測生產操作期間泄漏完整性損失方面將有局限性，因此重要的是要趨勢化泄漏完整性測試結果，以便這種CPP；關鍵過程參數可以在性能上進行評估，并針對偏差的影響進行風險評估
If negative pressure operation would be applied it follows to reduce the leak hole sizes in an isolation system to a level below which a cfu could not pass through (0.2 micron), the isolator barrier would need to act like a HEPA filter with high levels of leak integrity which are impractical for construction of pharmaceutical isolators used for aseptic
processing.
如果應用負壓操作，則需要將隔離系統的泄漏孔徑減小到cfu無法通過的水平（0.2微米），隔離器屏障需要像HEPA過濾器一樣具有高水平的泄漏完整性，這對于用于無菌處理的藥品隔離器的構建是不切實際的。
Qualification and routine monitoring of Pharmaceutical Isolator barrier leak integrity.
藥品隔離器屏障泄漏完整性的確認和常規監測
For reference; Classification according ISO 10648-2 – Generic standard for Containment Isolators.
參考；根據ISO 10648-2分類 - 密閉隔離器的通用標準。
PHSS Classification classes for Pharmaceutical Isolators including larger complex Aseptic processing Filling Isolators.
PHSS為藥品隔離器定義了五個隔離器屏障泄漏完整性等級，包括更復雜的無菌工藝灌裝隔離器。
The PHSS defines five classes of Isolator barrier leak integrity with each class corresponding to the relative %volume per hour leak rate:
PHSS定義了五種隔離器屏障泄漏完整性等級，每個等級對應于相對的每小時體積百分比泄漏率：
• 1% vol/h = PHSS Class 1
• 2% vol/h = PHSS Class 2
• 3% vol/h = PHSS Class 3
• 4% vol/h = PHSS Class 4
• 5% vol/h = PHSS Class 5
Therefore PHSS Class 1 leak integrity would correspond to the ISO 10648-2 Class 3 leak integrity.PHSS leak integrity classes are specific to Pharmaceutical isolators and not generic to all industries.
因此，PHSS 1級泄漏完整性將對應于ISO 10648-2的3級泄漏完整性。PHSS泄漏完整性等級特定于藥品隔離器，并不適用于所有行業。
Test pressures* a minimum of 2X the operating Isolator pressure should be applied as a test pressure with the minimum value also taking into account that following the allowable pressure decay the final test pressure should not be lower that the isolator operating pressure. High test pressures should be avoided to prevent unnecessary stress placed on sealing systems and the structure of the barrier system
測試壓力* 應將操作隔離器壓力的至少2倍作為測試壓力應用，最低值還應考慮在允許的壓力衰減之后，最終測試壓力不應低于隔離器操作壓力。應避免高測試壓力，以防止對密封系統和屏障結構造成不必要的壓力。
Test duration** the test durations should be kept short to avoid potential impact of temperature and barometric pressure fluctuations. In the case of the test pressure for integrity testing at the 5% vol/h leak integrity class the test duration could be reduced to 1 minute with an allowable pressure drop of 100 pascal if the test pressure is considered to be excessive in terms of applied stress to the isolator barrier when the 1.5 minute test duration is applied. There does need to be enough allowable margin from the test pressure to assure after pressure decay from leak testing the resulting pressure is no less than the intended operating pressure of the isolator.
測試持續時間** 測試持續時間應保持短暫，以避免溫度和氣壓波動的潛在影響。在5%/小時泄漏完整性等級的完整性測試中，如果認為1.5分鐘的測試持續時間對隔離器屏障施加的壓力過大，測試持續時間可以減少到1分鐘，允許的壓力下降為100帕斯卡。測試壓力需要有足夠的允許余量，以確保泄漏測試后的壓力衰減結果不小于隔離器的預定操作壓力。
Positive operating pressure pharmaceutical isolators should be pressure decay leak tested at a positive test pressure at a minimum of 2X the normal isolator operating pressure.
正壓操作的藥品隔離器應在正常隔離器操作壓力的至少2倍的正壓測試壓力下進行壓力衰減泄漏測試。
Negative pressure operation isolators must be qualified by pressure decay leak tests at a negative test pressure. In addition it may be useful to initially test, prior to commissioning, via an alternative test method to apply a positive test pressure so test agent e.g. ammonia, helium out leakage can be detected to assist diffused leakage assessments.
負壓操作隔離器必須在負壓測試壓力下通過壓力衰減泄漏試驗。此外，在調試之前，通過另一種測試方法（施加正測試壓力）進行初始測試可能是有用的，這樣可以檢測到測試劑(如氨、氦)的泄漏，以輔助擴散泄漏評估。
Integrated process machine integrity: By default integrity of machine bed plates applies as 1% vol/h (25 pascal allowable pressure drop over 1.5 minute test duration). At factory qualification testing (FQT and FAT) where filling machines may not be installed with the isolator and testing is completed with a dummy blank bed plate acceptance criteria for the Isolator barrier should be applied less 1% vol/h allowance for the machine bed plate sealing integrity that would form the complete barrier boundary later in Operational Qualification (OQ) studies
集成工藝設備的完整性：默認情況下，機器底板的完整性適用于1%/小時（1.5分鐘測試持續時間內允許的壓力下降為25帕斯卡）。在工廠資格測試（FQT和FAT）中，如果灌裝機器沒有與隔離器一起安裝，并且測試是使用虛擬空白底板完成的，則隔離器屏障的驗收標準應減去1%/小時的機器底板密封完整性，這將在操作資格（OQ）研究中形成完整的屏障邊界。
Qualification and routine monitoring leak integrity testing.
確認和常規監測泄漏完整性測試。
The values of test criteria in the PHSS leak integrity class tables are considered appropriate for qualification and routine monitoring however in principle a qualification test could pass with just a few pascal margin so considerations are required to assure robust margins in subsequent routine leak integrity monitoring. It is recommended either to consider more test pass margin at FQT/FAT testing to allow for inherent fluctuation in process operations (to allow for robust performance) or apply an extra margin of allowable pressure drop for routine monitoring to provide a more robust operating margin
PHSS泄漏完整性等級表中的測試標準值被認為適用于確認和常規監測，但原則上，確認測試可能僅以幾帕斯卡的余量通過，因此需要考慮確保在隨后的常規泄漏完整性監測中具有強大的余量。建議在FQT/FAT測試中考慮更多的測試通過余量，以允許工藝操作中的固有波動（以實現強大的性能），或在常規監測中應用額外的允許壓力下降余量，以提供更強的操作余量。
It is considered an extra 10 pascal of allowable pressure drop is justifiable in routine monitoring considering pressure monitoring device accuracy and small variations from reference devices during routine calibrations: Reference: EJPPS publication 2102; 17(3) 120- 125: An improved leak integrity rationale for Pharmaceutical isolators: Drinkwater, Triggs. Although this publication considers only small scale pharmaceutical/ pharmacy isolators the principles of the rationale are valid for larger scale isolators including filling lines.
額外的10帕斯卡的允許壓力下降在常規監測中被認為是合理的，考慮到壓力監測設備在常規校準期間的準確性和與參考設備的小變化：參考：EJPPS出版物2102；17（3）120-125：改進的藥品隔離器泄漏完整性理由：Drinkwater，Triggs。盡管這個出版物只考慮了小規模的藥品/藥房隔離器，但其理由的原則對于包括灌裝線在內的更大規模的隔離器是有效的。
In all cases a stabilization time should be applied before qualification/ routine pressure decay testing commences to allow for physical stabilization e.g. glove material stretching, barrier wall flexing as result of the applied test pressure. Stabilization times, typically a minimum of 1 minute, should be characterized for isolator systems where pressure decay testing is applied.
在所有情況下，在開始確認/常規壓力衰減測試之前，應該應用穩定時間，以允許物理穩定，例如手套材料拉伸，由于應用的測試壓力而使屏障壁彎曲。對于應用壓力衰減測試的隔離器系統，穩定時間通常至少為1分鐘。
During routine leak integrity testing if there is a marginal failure of integrity it is recommended to define (by procedure) a repeat leak test to account for potential temperature changes and a false fail result. If there is a rapid drop in pressure during testing with a slowing of pressure drop as the acceptance criteria is reached this often indicates a temperature impact (cooling of pressurised test air). Actual leaks tend to drop pressure more immediately and consistently.
在常規泄漏完整性測試中，如果存在邊緣完整性失敗，建議(通過程序)定義重復泄漏測試，以解釋潛在的溫度變化和錯誤的失敗結果。如果在測試過程中壓力迅速下降，并且達到驗收標準后壓力下降速度減慢，這通常表明溫度影響(加壓測試空氣冷卻)。實際泄漏往往會更迅速、更持續地降低壓力。
Leak integrity test automation and records.
泄漏完整性測試自動化和記錄
Automated pressure decay systems should ideally be integrated into the control system of the isolator barrier with test records including pass and fail results that meet data integrity requirements, included within the Isolator Batch / operating records. There should be risk based rationale to define the isolator leak integrity test parameters and associated acceptance criteria for qualification and routine integrity monitoring with details documented in the CCS (Contamination Control Strategy)
理想情況下，自動化壓力衰減系統應集成到隔離器屏障的控制系統中，測試記錄包括符合數據完整性要求的合格和不合格結果，包括在隔離器批次/操作記錄中。應該有基于風險的基本原理來定義隔離器泄漏完整性測試參數和相關的驗收標準，以確認和例行完整性監測，詳細信息記錄在CCS(污染控制策略)中。
Automation of the leak integrity test should include the automated closure of barrier dampers that form the controlled zone/ containment zone, management of integrated EM sampling systems (typically placing sample lines into a recirculation loop via a divert valve ahead of the particle counter and/or active air sampler) and closing of any isolator automated ‘Mouse holes’. In addition for isolators subjected to VHP/VH202 Bio-decontamination gloves need to be positioned on glove extenders (that are used for glove VHP exposure) so they are presented in a controlled manner for integrity testing. Gloves that hang loosely out of the isolator integrity during testing may be subjected to movement (dropping) during pressure decay providing a volume change that by default compensates the pressure drop and can change the test result to a more favourable but false outcome.
泄漏完整性測試的自動化應包括形成控制區/安全區的屏障阻尼器的自動關閉，集成EM采樣系統的管理(通常通過顆粒計數器和/或主動空氣采樣器前面的分流閥將樣品線放入再循環回路中)以及關閉任何隔離器的自動“老鼠洞”。此外，對于受VHP/VH202影響的隔離器，生物去污手套需要放置在手套擴展器上(用于手套VHP暴露)，以便以受控的方式呈現，以進行完整性測試。在測試過程中，松散地懸掛在隔離器完整性外的手套可能會在壓力衰減期間受到移動(掉落)的影響，從而提供默認情況下補償壓降的體積變化，并可能將測試結果更改為更有利但錯誤的結果。
Isolator integrity testing should be completed before implementing a VHP/VH202 cycle to ensure the isolator leak integrity CPP meets that defined at which Grade A conditions are established and the isolator is safe to contain VHP/VH202 once the bio-decontamination cycle is started. As a critical process parameter it is recommended the pre-production leak integrity test is applied as a control system ‘interlock’ so the control sequence will not advance to the VHP/VH202 cycle and on to production operations if the integrity test fails
隔離器完整性測試應在實施VHP/VH202循環之前完成，以確保隔離器泄漏完整性CPP符合建立a級條件的定義，并且一旦生物凈化循環開始，隔離器可以安全容納VHP/VH202。作為一個關鍵的工藝參數，建議將生產前泄漏完整性測試作為控制系統的“聯鎖”應用，這樣，如果完整性測試失敗，控制序列就不會進入VHP/VH202循環，也不會進入生產操作。
A post production/ batch isolator leak integrity test is recommended to confirm there was a steady state of leak integrity through production operations and support any route cause investigation as a result of a contamination event. After the automated pre-production Isolator leak integrity ‘interlock’ test further integrity tests should be selectable with rationale defined for the frequency
建議在生產/批次后進行隔離器泄漏完整性測試，以確認生產操作期間泄漏完整性的穩定狀態，并支持由于污染事件而進行的任何根本原因調查。在自動化生產前隔離器泄漏完整性“互鎖”測試之后，應可選擇進一步的完整性測試，并為頻率定義理由。
Barrier glove leak integrity is subject of separate PHSS guidance and should be undertaken separately to isolator barrier leak integrity testing (covered by this guidance) as the leak detection sensitivity for the full isolator volume is insufficient to detect single pin holes in gloves at around 100 micron diameter (the typical limit of detection for glove integrity test devices). Studies demonstrated it took 20 needle stick punctures of a barrier glove to fail an isolator leak integrity test at the PHSS Class 1 (1% vol/h) and ISO 10648-2 Class 3 (1% vol/h) leak test level.
屏障手套泄漏完整性是單獨的PHSS指導的主題，應與本指南涵蓋的隔離器屏障泄漏完整性測試分開進行，因為對于整個隔離器體積的泄漏檢測靈敏度不足以檢測手套中約100微米直徑的單個針孔（手套完整性測試設備的典型檢測限制）。研究表明，需要20次針刺穿透屏障手套，才能在PHSS 1級（1%/小時）和ISO 10648-2 3級（1%/小時）泄漏測試水平下使隔離器泄漏完整性測試失敗。
來源：GMP的那些事
