【導(dǎo)讀】本文檔提供了無菌原料藥生產(chǎn)加工有關(guān)的驗證指導(dǎo)。它借鑒了FDA和PhRMA以。前出版的無菌加工技術(shù)的概念和原則。這使得該文件可以為個人和。我們在這次修訂的目的是更新文件，以歸納6. 年來的行業(yè)經(jīng)驗，以及驗收標(biāo)準(zhǔn)的規(guī)定，這將在第1版中稱述。列舉一些美國FDA在其早期版本的回顧中提到的一些問題。原料藥生產(chǎn)中，無菌原料在數(shù)量和規(guī)模上的準(zhǔn)備，一般都需要相當(dāng)?shù)脑O(shè)備和過程，這與成品藥的制造有所不同。無菌原料生產(chǎn)方法的獨特，排除了用于無菌制劑的。這份技術(shù)報告以草案形式提前發(fā)布供公眾審查和評論。大多數(shù)提交的意見將被列。我們相信，這種方法實現(xiàn)了對文件最廣泛的審查，并確保作為一。個針對無菌原料藥的工藝模擬試驗領(lǐng)域的寶貴的指導(dǎo)性文件的合格性。應(yīng)被視為指南，而不是任何強制規(guī)定或標(biāo)準(zhǔn)。

　　

【正文】 ges. Materials that inhibit microbiological growth should not be used. If a test material is utilized, a further decision between a liquid or powder material is also required. Those firms that have chosen to segment the process simulation according to the various unit operations may elect to make different selections for the test material in different parts of their overall program. For example, in sterile BPC simulations with a crystallization step, a liquid material may be used during simulation of the early steps, and a powder material in those steps which follow the crystallization step. 不管決定是模擬整個無菌工藝或部分單元操作的形式，應(yīng)考慮模擬使用的物料的選擇。選擇是：促進(jìn)微生物生長的培養(yǎng)基，安慰劑物料，無物料模擬或?qū)嶋H產(chǎn)品物料 （通常為輔料）。每種選擇都有一定的優(yōu)點和缺點。不能使用抑制微生物生長的物料。如果選擇了一種測試物料，進(jìn)一步需要決定選擇液體或粉末物料。那些決定按照不同的單元操作將工藝模擬分開的公司，可能需要在整個方案中的不同部分選擇不同的測試物料。例如，帶有結(jié)晶工序的無菌原料藥模擬，在早期步驟模擬階段可能需要液體物料，而結(jié)晶工序后的步驟需要粉末物料。 Inherent in the selection of a test material, and the decision to use a test material at all are considerations of potential adverse affects implicit in the use of a material. As a general rule, nothing should be introduced into the system, whether media or placebo, which may present a problem in subsequent processing. The material (if used) must be able to be easily removed from the equipment in order to prevent an increased potential for contamination of production materials that would later enter the system. 在選擇測試物料時的一個內(nèi)在問題，決定究竟使用哪種測試物料，需要考慮物料使用時的潛在副作用。一般原則，不能在系統(tǒng)中引入任何物質(zhì)，不管是培養(yǎng)基或安慰劑，可能在隨后的加工中帶來問題。 為防止增加隨后進(jìn)入系統(tǒng)的產(chǎn)品物料的潛在污染，使用的物料必須能從設(shè)備上容易移除。 See Appendix 1 for information on the selection, sterilization and use of test materials. 見附錄 1測試物料選擇、滅菌和使用的信息。 . Growth Medium Simulations 培養(yǎng)基模擬 A microbial growth medium in either liquid or solid state is processed in lieu of the production materials. The microbiological growth media may be tested for microbial count or sterility depending upon the acceptance criteria requirements in the protocol. 使用液體或固體狀態(tài)的微生物培養(yǎng)基來代替生產(chǎn)物料。微生物生長培養(yǎng)基 可進(jìn)行微生物計數(shù)或無菌測試，由方案中要求的可接受標(biāo)準(zhǔn)決定。 Advantages 優(yōu)點 ? Allows for the direct evaluation of the aseptic processing procedures. 允許無菌加工程序的直接評價。 ? Less reliance on environmental conditions in the evaluation of the process. 在工藝評價時較少依賴于環(huán)境條件。 Disadvantages 缺點 ? The microbiological growth media may be overly sensitive to antibiotic materials and other innately inhibitory materials. The use of deactivating enzymes may be necessary, however their utility in large systems may be severely limited. 微生物培養(yǎng)基可能對抗菌性物料和其他先天性抑菌物料過于敏感。可能需要使用滅活酶，但是他們在大系統(tǒng)中的使用可能嚴(yán)格受限。 ? Cleaning of the process equipment after exposure to the microbiological growth media may represent a new cleaning procedure which must be developed and validated. 工藝設(shè)備在暴露于微生物培養(yǎng)基后進(jìn)行清洗，可能提出了一個必須開發(fā)和驗證的新的清洗程序。 ? It adds increased risk of microbiological contamination of the facility by providing a major nutrient source when normal materials used may be innocuous or bactericidal. 另外，由于提供了一個營養(yǎng)來源，增加了設(shè)施微生物污染的風(fēng)險， 而正常使用的物料可能是無害的或殺菌的。 ? Detection of contamination in large containers may be difficult. 在大容器中檢測污染可能比較困難。 ? Quantities of microbiological growth media required may be excessive. 可能需要大量的微生物培養(yǎng)基數(shù)量。 ? Process simulation may have little resemblance to the actual process because of concerns regarding the media39。s growth promotion capability under routine operating conditions within the equipment. 由于關(guān)系到設(shè)備內(nèi)在正常操作條件下的培養(yǎng)基的促生長能力，工藝模擬與實際工藝可能很少有類似之處。 ? Process gases should be replaced with air to enhance microbial recovery. 工藝氣體由能促進(jìn)微生物回收率的空氣代替。 . Placebo Material Simulation 安慰劑物料模擬 A placebo material is substituted for the production materials and handled in a representative manner. The placebo material can be sampled for microbial count or sterility testing depending upon the acceptance criteria requirements of the protocol. 使用安慰劑物料來代替生產(chǎn)物料，以一種特定的方式處理。安慰劑物料可取樣用來 進(jìn)行 微生物計數(shù)或無菌測試，由方案中要求的可接受標(biāo)準(zhǔn)決定。 Advantages 優(yōu)點 ? Can use materials which are able to tolerate the actual processing conditions utilized in the aseptic process. 可使用 能 忍受無菌工藝使用的實際加工條件 的物料。 ? Placebo materials can be chosen such that their removal from the processing equipment after the simulation can be readily acplished. 可選擇安慰劑物料，容易實現(xiàn)在模擬后從加工設(shè)備上移除。 ? Placebo materials can be substantially less expensive than product or microbiological growth media, which can be a significant concern in large process equipment. 安慰劑物料的成本遠(yuǎn)低于產(chǎn)品或微生物生長培養(yǎng)基， 在 較大的工藝設(shè)備中是顯著關(guān)注點。 ? Some of the actual materials utilized in the aseptic process may be utilized. 可 使用 在無菌工藝中 實際使用的某些物料 。 Disadvantages 缺點 ? Sterility or microbial count testing must be performed in order to assess whether any microanisms are present. 必須執(zhí)行無菌或微生物計數(shù)測試，以評估是否存在微生物。 ? Cleaning of the process equipment after exposure to the placebo may represent a new cleaning procedure which must be developed and validated. 生產(chǎn)設(shè)備在暴露給安慰劑后的清潔表明，必須進(jìn)行新清潔程序的執(zhí)行和驗證。 ? The placebo material must be evaluated for lack of inhibitory effects on microanisms. 安慰劑原料必須進(jìn)行對微生物無抑制效應(yīng)的評估。 ? The sterilization of powder placebos must be validated. 粉末安慰劑的滅菌 必須驗證。 ? Testing of large quantities of material may be required. 可能需要對大量的原料進(jìn)行測試。 . Simulation Without Material 無物料模擬 This is a simulation performed in the absence of materials. This approach has been used to evaluate operating procedures and personnel performing discrete aseptic manipulations, ., subdivision into final containers. The aseptic production processes are simulated using the procedures, personnel, equipment and ponents ordinarily utilized in the aseptic process. Immediately after pletion of the simulation, extensive microbial sampling of product contact surfaces and personnel is performed. Alternatively or in addition, a flush of the process train with a suitable medium can be employed. The surface sampling results are utilized to determine microb