【正文】 I 摘 要 研究背景：特寶生物公司擬采用模塊化的布局理念， 在一個(gè)復(fù)合的制劑車間中整合西林瓶注射液 /凍干粉針和預(yù)充注射器注射液兩條無菌生產(chǎn)線，為 10 個(gè)左右的重組蛋白質(zhì)藥物提供規(guī)范、高效、低成本的制劑生產(chǎn)車間。同時(shí)這些產(chǎn)品還要銷往中國以外的亞洲、美洲、歐洲和非洲等地區(qū)，面臨多個(gè)國家和地區(qū)的法規(guī)監(jiān)管要求，因此需要依據(jù)最新的 GMP 發(fā)展趨勢(shì)，按無菌風(fēng)險(xiǎn)和對(duì)產(chǎn)品質(zhì)量影響程度，重點(diǎn)構(gòu)思和梳理工藝布局，找到優(yōu)化的方案，并對(duì)關(guān)鍵風(fēng)險(xiǎn)環(huán)節(jié)進(jìn)行針對(duì)性處理。 研究過程：通過法規(guī)評(píng)價(jià)和產(chǎn)品分析，找到影響車間布局的關(guān)鍵因素為產(chǎn)品特 性和工藝流程。而對(duì)于緊湊型多生產(chǎn)線的布局，軋蓋區(qū)域的選擇和布局是歐盟和中國GMP 法規(guī)關(guān)注的焦點(diǎn)之一。通過對(duì) 3 種典型布局的物料流程和人員流程以及無菌風(fēng)險(xiǎn)控制進(jìn)行了分析，選擇了比較嚴(yán)格的車間布局。對(duì)于影響無菌車間布局的軋蓋工藝設(shè)計(jì)，采用了 B 級(jí)背景的層流保護(hù) 的方案，設(shè)計(jì)了正壓保護(hù)的捕塵系統(tǒng)，最大程度減少空間需求和投資和運(yùn)行管理成本。 研究結(jié)論：多品種重組蛋白質(zhì)藥物制劑生產(chǎn)車間兩條無菌生產(chǎn)線的設(shè)計(jì)、安裝和驗(yàn)證符合 “質(zhì)量源于設(shè)計(jì) ”和 “質(zhì)量風(fēng)險(xiǎn)管理 ”等最新的 GMP 理念，投產(chǎn)后產(chǎn)能可以達(dá)到3000 多萬支的目標(biāo)。 關(guān)鍵 詞： 重組蛋白質(zhì)藥物；無菌軋蓋； RABS；正壓捕塵系統(tǒng) II The Choice of Sealing Machine and the Influence for the Aseptic Facilities Layout of Multi Rebinant Protein Drugs Abstract Research Background: Amoytop Biotech pany adopts modular concept to design the layout for an aseptic multiproducts preparation facility, which integrates two aseptic filling lines for about ten rebinant protein drugs, including the vial injection/freezedried product and the prefilled syringe injection, into one facility, to provide a preparation workshop with pliance, high efficiency and low cost. As these products will be marketed to other regions, such as Asia, America, Europe and Africa, besides China, it is inevitable that the regulatory requirements of other countries and regions will be taken into consideration. On the basis of the latest cGMP requirement, according to the aseptic risk level and the impact to the product’s quality, Amoytop focuses on the design and arrangement of process layout, optimizes the scheme, and adopts the strategy aiming at the key risk elements. Research Process: Through the regulations evaluation and product analysis, the product characteristics and process are found to be the key factors which might influence workshop layout. For the pact production line layout, the selection and layout of aseptic sealing region is one of the concerns of European Union and Chinese GMP regulations. Through analyzing three typical layouts of the material flow, personnel flow and aseptic risk assessment, the relatively strict workshop layout is chosen. Considering the impact on the aseptic layout from sealing process, Amoytop uses the laminar air flow protecting scheme with grade B background, and designs the positive pressure protecting dust collecting system resulting in minimizing the space requirement, investment and operation management costs. Research Conclusion: The design, installation and qualification of the multirebinant protein drug preparation workshop ply to the latest cGMP concept, . Quality by Design and Risk Management, thus it finally reaches targeting annual output for more than 30 million vials. Keywords: rebinant protein drug, aseptic sealing, RABS, positive pressure dust collecting system 目 錄 第 1 章 引言 ..................................................................................................................................... 1 III 研究背景 .................................................................................................................................... 1 項(xiàng)目情況和研究目標(biāo) ................................................................................................................ 3 關(guān)鍵詞 ...................................................................................................................................... 4 第 2 章 無菌制劑生產(chǎn)車間布局的影響因素分析 ..................................................................... 5 GMP 法規(guī)對(duì)無菌車間設(shè)計(jì)要求 ............................................................................................... 5 無菌注射工藝制劑生產(chǎn)車間布局的考慮 ................................................................................. 7 重組蛋白質(zhì)藥物多品種無菌制劑生產(chǎn)車間布局的影響因素分析 ......................................... 9 重組蛋白質(zhì)藥物多品種無菌制劑生產(chǎn)車間布局的挑戰(zhàn)性因素 .......................................... 12 第 3 章 不同無菌車間的布局與軋蓋工藝的挑戰(zhàn) ..................................................................... 13 中國和歐盟 GMP 規(guī)范關(guān)于軋蓋的觀點(diǎn) ............................................................................... 13 軋蓋工藝布局的設(shè)計(jì)與選擇 .................................................................................................. 15 模式 A： 軋蓋跟配液等在同一非無菌區(qū)域內(nèi)進(jìn)行 ......................................................... 15 模式 B：軋蓋位于單獨(dú)的軋蓋區(qū)域 ................................................................................... 16 模式 C： 軋蓋位于無菌區(qū)域 ............................................................................................... 18 三種無菌車間布局模式與軋蓋工藝選擇 ........................................................................... 20 第 4 章 軋蓋過程的環(huán)境控制 ..................................................................................................... 24 軋蓋產(chǎn) 品保護(hù) .......................................................................................................................... 24 傳統(tǒng)捕塵系統(tǒng) .......................................................................................................................... 25 FFU 捕塵系統(tǒng) .......................................................................................................................... 26 正壓保護(hù)的 FFU 捕塵系統(tǒng) .................................................................................................... 28 第 5 章 軋蓋設(shè)計(jì)主要實(shí)施結(jié)果的確認(rèn) ..................................................................................... 31 第 6 章 研究結(jié)論 ........................................................................................................................... 35 1 第 1章 引言 研究背景 上世紀(jì) 80 年代 初 ， 用重組 DNA 技術(shù) 獲取的第一 個(gè)重組人胰島素在美國上市以來 ， 以 細(xì)胞因子 類為主的重組蛋白質(zhì) 藥物在全球醫(yī)藥市場(chǎng)占據(jù)了很大的份額 [1]；雖然 經(jīng)過 將近 30 年的發(fā)展， 但由于其在很多疾病治療方面不可替代的作用，安全性和有效性得到實(shí)踐檢驗(yàn)，這些藥物在全球藥物 市場(chǎng) 的份額仍在 不斷擴(kuò)大 ； 同時(shí)近年不少專利藥物陸續(xù)到期，為非原創(chuàng)企業(yè) 在世界主要藥物市場(chǎng)的 合法 “仿制 ”生產(chǎn)提供了機(jī)會(huì) [2]，到 2022 年 之前，將有重組人生長(zhǎng)激素、重組人胰島素、重組人鏈激酶、重組人尿激酶、重組人組織纖溶酶原激活劑、重組人干擾素 α、重組人干擾素 γ、重組人介素 重組人紅細(xì)胞生成素和重組人粒細(xì)胞刺激因子等十多種生物藥物專利到期 [3]。 由于重組蛋 白質(zhì)藥物研究