【文章內(nèi)容簡介】 s environmental monitoring, qualification of personnel and validation of cleaning and sterilization cycles, it is possible to maintain the level of asepsis demonstrated during the process simulation test. 但是，通過控制和相關(guān)的進程的驗證，如環(huán)境監(jiān)測，人員評估和清洗驗證以及消毒周期驗證，它有可能在這個工藝模擬測試中保持無菌水平。 Therefore, it is important to validate the related sanitization and sterilization processes independently, such as sterilization/depyrogenation of the product, sterilization of the process equipment including product contact surfaces, sterilization of containers (intermediate and final packaged bulk), and support systems such as air, water, or nitrogen (6, 7, 8). 因此，重要的是要獨立驗證相關(guān)的消毒和滅菌過程， 例如滅菌 /產(chǎn)品的除熱原，工藝設備的滅菌，包括產(chǎn)品接觸表面，容器的滅菌（中間產(chǎn)品和最終包裝），支持系統(tǒng)，如空氣，水，或氮（ 6， 7， 8）。 Confidence in the sterility of a specific production lot is gathered through a number of process controls and procedures including: documented and validated sterilization/sanitization procedures, inprocess controls regulating the production process, environmental monitoring, prehensive batch records, extensive qualification of process equipment, and training of operating personnel. 對一個具體生產(chǎn)批次的無菌的確信是通過過程控制和程序的序列號來收集，包括：被記載和驗證過的殺菌 /消毒程序，對 生產(chǎn)過程監(jiān)察的實時過程控制，環(huán)境監(jiān)測，全面記錄，工藝設備的全方位條件，和培訓操作人員。 2. PROCESS SIMULATION CONCEPTS AND PRINCIPLES 工藝模擬的概念和原理 . Number and Frequency of Tests 實驗的次數(shù)和頻率 For a new facility or production process, process simulations can be performed as part of the overall validation. Initial process simulation tests, if performed, are conducted after equipment qualification, sterilization process validation, and personnel training have been performed, and environmental monitoring has demonstrated that the new facility is under the desired state of control (9, 10, 11). If a process simulation test fails in the absence of this supportive work, identification of a possible root cause will usually be more difficult. Three consecutive successful process simulation tests are performed when evaluating a new facility or process. Prior to release of the new facility, or new process for production use, acceptable results from these process simulation tests should be achieved to demonstrate the reproducibility of the process. 對應一個新的設施或 生產(chǎn)工藝，工藝模擬應該作為所有驗證的一部分。最初的工藝驗證應該在設備確認、滅菌工藝驗證、人員培訓已經(jīng)完成并且環(huán)境監(jiān)測證明新的設施已經(jīng)在預期的狀態(tài)中受控之后進行 (9, 10, 11)。如果沒有作這些支持性的工作，工藝模擬實驗失敗的話，將很難確定可能的原因。當確認一個新的設施或工藝時，驗證一個工藝應該進行三次連續(xù)成功的模擬工藝實驗。在為生產(chǎn)使用正式批準一個新的設施、新的工藝之前，應該完成這樣連續(xù)的可接受的結(jié)果，以證明工藝的可重復性。 In existing facilities, a process simulation test program should be considered for each aseptic process. Additional process simulation tests may be considered to evaluate changes to procedures, practices or equipment configuration (See Section 11— Periodic Reassessment). 在現(xiàn)有設施，過程模擬測試程序應被考慮到每 個無菌過程。追加工藝模擬試驗可被用來評估程序、實踐或設備配置的變更（見第 11期再評估表）。 Process simulations for closed systems can be performed after sterilization to confirm the acceptable sterilization of the systems as well as the appropriateness of the procedures employed within. The duration of campaigns for closed system may be established through physical monitoring of such aspects as pressure differentials, leak rates, filter integrity tests, etc. and is further supported by a preventive maintenance program. End of campaign process simulations are thus not required for the closed portions of a process system. The duration of campaigns for open systems may be confirmed through appropriate process simulations conducted at the end of a real or simulated campaign. 封閉系統(tǒng)的過程模擬可以在滅菌后實施，以確認該系統(tǒng)的滅菌合格性以及內(nèi)部程序的適當性。在封閉系統(tǒng)的工作持續(xù)時間可能將通過如壓力差，泄漏率，過濾器完整性測試等物理等方面的監(jiān)測來被確定，并進一步被預防性維修計劃所支持。 工作過程模擬的完成不需要一個工藝系統(tǒng)的封閉部分。開放系統(tǒng)的工作持續(xù)時間可能通過真實或模擬的工作結(jié)束時進行的適當?shù)墓に嚹M來被確認。 . Worst Case 最差條件 One of the more prevalent techniques used in the validation of pharmaceutical processes is the employment of worst case scenarios. 在制藥工藝驗證中最常采用的技術(shù)之一是采用“最差條件”。 The use of worst case situations is intended to provide a greater challenge to the process, system or equipment being validated than that experienced under routine processing “最差條件” 是有意對工藝、系統(tǒng)、設備在更高的挑戰(zhàn)條件下進行驗證。 If, under the circumstances of the worst case challenge, acceptable results are achieved, then there is greater confidence in the reliability of the system under more normal situations. 如 果在“最差條件”的挑戰(zhàn)下，仍能夠達到預期的可接受標準，那么在正常條件下，對系統(tǒng)的可靠性將有更高的信心。 Process simulation tests readily lend themselves to worst case challenges. Some of the types of challenges which may be employed where possible are: 工藝模擬實驗很容易進行“最差條件”的挑戰(zhàn)。下面提供了一些類型的挑戰(zhàn)： ? using materials, equipment, utensils and other items which have remained in the aseptic processing area for extended periods after sterilization。使用的原料、設備、器具等在滅菌后于無菌工藝區(qū)保留時間超出期限。 ? using the maximum number of personnel necessary to process the batch。 使用人員數(shù)超過灌裝工藝所需。 ? increasing the time period between the pletion of equipment sterilization and the start of the process simulation。 設備消毒的完成與開始模擬之間時間間隔過長 ? using a growth promoting medium or placebo material in the process simulation test rather than an inhibitory material。 在工藝模擬實驗中使用促生長培養(yǎng)基或安慰劑，而不是使用有抑制性的處方。 ? performing a process simulation test after pletion of the last lot in a production campaign。 在最后的生產(chǎn)完成后進行工藝模擬實驗 。 The conduct of a process simulation for a sterile bulk typically includes activities and manipulations that are specific for its execution. 對于無菌原料的工藝模擬的進行通常包括大量特定的活動和操作。 These added steps introduce a higher potential for contamination than is inherent in the routine process and pose an increased risk for process simulation failure. 相比固有的常規(guī)工藝，這些額外的步驟導 致了更高的潛在污染，增加了過程模擬失敗的風險。 In the development of protocols or procedures used for the definition of process simulation tests, the use of worst case challenges such as those described above is an essential element of a wellfounded program. 在建議用于定義工藝模擬試驗的方案 或過程時，一個有良好根據(jù)的程序會使用上面提到的“最差條件”的挑戰(zhàn)。T