【生产管理】利巴韦林注射液生产工艺验证方案(DOC 42页)

(10)申请公布号 (43)申请公布日 2014.08.27C N 104000778A (21)申请号 201410277520.7(22)申请日 2014.06.20201410273720.5 2014.06.18 CNA61K 9/08(2006.01)A61K 31/7056(2006.01)A61P 31/12(2006.01)(71)申请人海南通用康力制药有限公司地址570311 海南省海口市南海大道269号(72)发明人王志涛 林小雪 张丽华(74)专利代理机构广州三环专利代理有限公司44202代理人郝传鑫(54)发明名称利巴韦林注射液及其制备方法(57)摘要本发明公开一种利巴韦林注射液的制备方法，包括以下步骤：a 、将利巴韦林和甘露醇加入部分注射用水中搅拌溶解，然后将注射用水加至总配制量；b 、加入总配制量0.1％的活性炭在室温下搅拌30分钟，过滤至澄明，经微孔为0.22μm的滤膜过滤成滤液；c 、将步骤b 中的所述滤液经过PH 值检测，取PH 值符合注射液要求的所述滤液1.25ml 装入7ml 的管制瓶中，然后半压塞；d 、将步骤c 中的管制瓶放入冷冻干燥机中冷冻干燥17-19小时，然后进行全压塞、扎盖及包装。

本发明同时公开了使用上述方法制得的利巴韦林注射液，所述巴韦林注射液具有纯度高、产品稳定性好及药用效果好等优点。

(66)本国优先权数据(51)Int.Cl.权利要求书1页 说明书3页(19)中华人民共和国国家知识产权局(12)发明专利申请权利要求书1页 说明书3页(10)申请公布号CN 104000778 A1/1页1.一种利巴韦林注射液的制备方法，其特征在于，包括以下步骤：a 、将利巴韦林和甘露醇加入部分注射用水中搅拌溶解，然后将注射用水加至总配制量；b 、加入总配制量0.1％的活性炭在室温下搅拌30分钟，过滤至澄明，经微孔为0.22μm 的滤膜过滤成滤液；c 、将步骤b 中的所述滤液经过PH 值检测，取PH 值符合注射液要求的所述滤液1.25ml 装入7ml 的管制瓶中，然后半压塞；d 、将步骤c 中的管制瓶放入冷冻干燥机中冷冻干燥处理17-19小时，然后进行全压塞、扎盖及包装。

制药工程课程设计设计题目：年产2亿支2ml水针剂生产车间工艺设计专业班级：姓名：学号：小组成员：指导老师：设计时间：摘要本文是对年产2亿支2ml，200mg利巴韦林水针剂生产车间工艺设计的详细说明。

一方面，根据任务要求，对工艺流程进行了说明，并绘制了工艺管道流程图，完成了物料衡算和设备选型。

另一方面，按照GMP的要求，设计工艺平面布置，并绘制了平面压差分布图和洗瓶工序的管道布置图。

本设计严格遵守GMP规定，符合安全、环保、技术经济等方面的要求。

关键词：水针剂平面布置联动机组洁净区GMP目录一、工艺概述水针剂的生产步骤主要包括原辅料的准备、配制、灌封、灭菌、质检、包装等环节。

本设计的原料是药用利巴韦林（2ml，200mg），辅料是注射用水。

选择中性玻璃安瓿作为注射液的容器。

水针剂的洁净区划分：注射用水的制备、理瓶、检漏灭菌、灯检、印字包装在一般生产区；原料的配制、粗滤、安瓿的粗洗、精洗在C级洁净区；原料液的精滤、安瓿干燥灭菌、冷却、灌装、封口位于B级洁净区。

（一）工艺流程框图1.1 工艺流程框图（二）工艺用水制备水针剂生产需要大量的纯化水及注射用水。

本工艺中以自来水为原水，首先进行预处理，包括机械过滤、活性碳过滤、保安过滤，然后经过二级渗透处理得到纯化水，纯化水再经紫外线杀菌、微孔过滤后至用水点。

纯化水经过多效蒸馏操作得到蒸馏水，蒸馏水保温循环贮存，蒸馏水经过0.45μm微孔膜过滤即可送至注射用水的用水点。

1、纯化水制备目前在制药企业生产中，纯化水的制备一般有以下四种工艺流程：1)原水→ 预处理→ 阳离子交换→ 阴离子交换→ 混床→ 纯化水2)原水→ 预处理→ 电渗析→ 阳离子交换→ 阴离子交换→ 混床→ 纯化水3)原水→ 预处理→ 一级高压泵→ 一级反渗透→ 二级高压泵→二级反渗透→ 纯化水4)原水→ 预处理→高压泵→反渗透→ 一级混床→ 二级混床→纯化水其中全离子交换用于符合饮用水标准的原水，常用于原水含盐量<500 mg/L；电渗析+离子交换常用于原水含盐量>500 mg/L，使用电渗析，可减少树脂频繁再生，减少离子交换负担，使树脂制水周期延长，减少再生时酸、碱用量和排污量；反渗透+离子交换以反渗透直接作为二级混床的前处理，此时为了减轻混床再生时碱液用量，需在混床前设置脱气塔以脱去CO2。

利巴韦林检验标准操作规程(外标法)文件名称利巴韦林检验标准操作规程文件编码版本号00制定人部门审核质量保证部审核批准人制定日期审核日期审核日期批准日期颁发部门质量保证部生效日期年月日分发部门质量保证部、质量控制部1.目的：指导检验人员掌握正确的操作方法，以确保检测结果的准确性和可靠性。

2.适用范围：仅适用于本公司。

3.责任：质量控制部经理、化验室主任、化验员。

4.标准依据：利巴韦林内控质量标准5.内容：5.1.【性状】5.1.1.标准规定：本品为白色或类白色结晶性粉末；无臭，无味。

5.1.1.1.仪器：偏光显微镜，载玻片5.1.1.2.试液：液状石蜡5.1.1.3.操作方法：取本品少许，置载玻片上，加液状石蜡1滴使悬浮，在偏光显微镜下检视。

观察转动载物台时，是否呈现消光位和双折射现象，进行结晶性判断。

5.1.1.4.结果与判定：根据所观察的供试品外观与转动载物台时，是否呈现消光位和双折射现象进行判断，与上述描述相符者，判为结晶性粉末。

5.1.2.标准规定：本品在水中易溶，在乙醇中微溶，在乙醚或二氯甲烷中不溶。

5.1.2.1.用具：小试管5.1.2.2.试剂：乙醚、乙醇、二氯甲烷5.1.2.3.操作方法：称取研成细粉的供试品，置于 25℃±2℃一定容量的溶剂中，每隔5分钟强力振摇30秒钟；观察30分钟内的溶解情况，如无目视可见的溶质颗粒时，即视为完全溶解。

5.1.2.4.结果与判定：本品在水中易溶，在乙醇中微溶，在乙醚或二氯甲烷中不溶，判为符合规定；否则，判为不符合规定。

文件编码版本号005.1.3.比旋度5.1.3.1.标准规定：40mg/ml的水溶液比旋度为-35.0o至－37.0o。

5.1.3.2.仪器与用具：分析天平、旋光仪、温度计5.1.3.3.操作方法5.1.3.3.1.取本品2.0g，精密称定，置50ml容量瓶中，加水稀释至刻度，制成每1ml中约含40mg的溶液，摇匀，使供试品溶液的温度控制在20℃±0.5℃。

[19]中华人民共和国国家知识产权局[12]发明专利申请公开说明书[11]公开号CN 1368553A [43]公开日2002年9月11日[21]申请号02115486.4[21]申请号02115486.4[22]申请日2002.01.30[71]申请人武汉大学地址430072湖北省武汉市武昌珞珈山[72]发明人陈蔚梅 冯胜彦 郭明雄 艾建宇 吴斌熊晓然 吴显辉 [74]专利代理机构武汉科宏专利事务所代理人王敏锋[51]Int.CI 7C12P 19/28权利要求书 1 页 说明书 8 页[54]发明名称一种抗病毒药物利巴韦林的制备方法[57]摘要本发明公开了一种抗病毒药物利巴韦林的制备方法。

采用乙酰短杆菌ATCC39311菌株,以淀粉、蛋白胨、牛肉膏、氯化钠、磷酸氢二钾、磷酸二氢钾、消泡剂、自来水为原料,然后进行发酵,以所得完整菌体为酶源,以肌苷作为核糖供体合成利巴韦林。

本发明工艺简便,方法易行,作为酶源的细菌发酵时间短,生产成本低廉,产物得率高,便于储存和重复使用。

02115486.4权 利 要 求 书第1/1页1.一种抗病毒药物利巴韦林的制备方法，包括下列步骤：A、酶源菌体发酵培养基的配制：淀粉0.1％～2.0％，蛋白胨0.2％～1.0％，牛肉膏0.05％～0.5％，氯化钠0.01％～0.12％，磷酸氢二钾0.33％，磷酸二氢钾0.10％，消泡剂0.02％，自来水95.95％～99.19％，发酵液pH值控制在7.0-8.5；B、酶源菌体的发酵：采用发酵罐；空气流量为1∶0.8～1∶1.5；罐压为0.02MPa～0.05MPa；发酵温度为28℃～32℃；种子培养基及发酵工艺控制与一般发酵控制条件相同；发酵时间为16小时～22小时；C、酶源菌体的发酵后处理：细菌出罐经离心分离后，于磷酸缓冲液重悬，备用；D、底物反应：酶反应底物为：肌苷和三氮唑甲酰胺；酶反应底物浓度分别为10m m o l/L ～200mmol/L；投料比：肌苷∶三氮唑甲酰胺＝1∶1～1∶1.5；酶用量：60mg～200mg 湿菌体/ml反应液；反应条件：65℃，24小时；E、产物的分析测定：反应结束后，离心分离菌体，取上清反应液，用高效液相色谱法检测。

长治市三宝生化药业有限公司编号SBB2.8.5.6利巴韦林注射液生产工艺验证方案长治市三宝生化药业有限公司方案制订签名日期方案会签签名日期生产技术部签名日期验证小组签名日期方案批准质量保证部日期目录1.概述`````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````4` 1.1.产品简述``````````````````````````````````````````````````````````````````````````````````````````````````````````````4 1.2.处方及依据``````````````````````````````````````````````````````````````````````````````````````````````````````````41.3.生产工艺流``````````````````````````````````````````````````````````````````````````````````````````````````````````5`2.验证目的````````````````````````````````````````````````````````````````````````````````````````````````````````````````````53.验证的范围```````````````````````````````````````````````````````````````````````````````````````````````````````````````64.验证各部门职责及组织结构```````````````````````````````````````````````````````````````````````````````65.验证准备````````````````````````````````````````````````````````````````````````````````````````````````````````````````````76.验证内容及实施``````````````````````````````````````````````````````````````````````````````````````````````````````8` 6.1.洗瓶工序````````````````````````````````````````````````````````````````````````````````````````````````````````````8 6.2.配制工序```````````````````````````````````````````````````````````````````````````````````````````````````````````12 6.3.灌封工序```````````````````````````````````````````````````````````````````````````````````````````````````````````15 6.4.灭菌工序```````````````````````````````````````````````````````````````````````````````````````````````````````````206.5.灯检工序```````````````````````````````````````````````````````````````````````````````````````````````````````````246.6.包装工序```````````````````````````````````````````````````````````````````````````````````````````````````````````266.7.成品检验结果``````````````````````````````````````````````````````````````````````````````````````````````````287.偏差分析``````````````````````````````````````````````````````````````````````````````````````````````````````````````````298.验证结论``````````````````````````````````````````````````````````````````````````````````````````````````````````````````299.附表````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````299.1. 设备一览表及生产能力```````````````````````````````````````````````````````````````````````````````309.2.设备性能验证确认及检查情况表```````````````````````````````````````````````````````````````319.3参加验证人员培训情况检查表````````````````````````````````````````````````````````````````````329.4.厂房与公用设施验证的确认和检查情况表`````````````````````````````````````````````349.5.空气净化系统、工艺用水系统验证的确认和检查情况表`````````````````359.6.计量器具检查情况表```````````````````````````````````````````````````````````````````````````````````````369.7.三批（按四批准备）验证使用的原料、辅料和安瓿供应商确认及检查情况表`````````````````````````````````````````````````````````````````````````````379.8.质量检验系统验证和准备情况表```````````````````````````````````````````````````````````````389.9.检验仪器检查情况表``````````````````````````````````````````````````````````````````````````````````````399.10检验试剂检查情况表````````````````````````````````````````````````````````````````````````````````````409.11质量监控点、监控内容、监控方法、监控频次表`````````````````````````````411.概述1.1.利巴韦林注射液（1ml：100mg）常温状态下是无色的澄明液体，属抗病毒药，用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎。

利巴韦林工艺验证利巴韦林注射液生产工艺验证方案长治市三宝生化药业有限公司方案制订签名日期方案会签签名日期生产技术部签名日期验证小组签名日期方案批准质量保证部日期目录1.概述``````````````````````````````````````````````````````````````````````````````````` ``````````````````````````````````````````4``````````````````````````````````````41.2.处方及依据``````````````````````````````````````````````````````````````````````` ```````````````````````````````````41.3.生产工艺流``````````````````````````````````````````````````````````````````````` ```````````````````````````````````5`2.验证目的````````````````````````````````````````````````````````````````````````````` ```````````````````````````````````````53.验证的范畴`````````````````````````````````````````````````````````````````````````` `````````````````````````````````````64.验证各部门职责及组织结构```````````````````````````````````````````````````` ```````````````````````````65.验证预备````````````````````````````````````````````````````````````````````````````` ```````````````````````````````````````76.验证内容及实施``````````````````````````````````````````````````````````````````` ```````````````````````````````````8`6.1.洗瓶工序````````````````````````````````````````````````````````````````````````` ```````````````````````````````````86.2.配制工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````126.3.灌封工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````156.4.灭菌工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````206.5.灯检工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````246.6.包装工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````26```````````````````````````````287.偏差分析````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````298.验证结论````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````299.附表``````````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````````299.1. 设备一览表及生产能力````````````````````````````````````````````````````` ``````````````````````````309.2.设备性能验证确认及检查情形表``````````````````````````````````````````` ````````````````````319.3参加验证人员培训情形检查表`````````````````````````````````````````````` ``````````````````````329.4.厂房与公用设施验证的确认和检查情形表``````````````````````````````` ``````````````349.5.空气净化系统、工艺用水系统验证的确认和检查情形表````````````` ````359.6.计量器具检查情形表`````````````````````````````````````````````````````````` `````````````````````````````369.7.三批（按四批预备）验证使用的原料、辅料和安瓿供应商确认及检查情形表```````````````````````````````````````````````````` `````````````````````````379.8.质量检验系统验证和预备情形表``````````````````````````````````````````` ````````````````````389.9.检验仪器检查情形表`````````````````````````````````````````````````````````` ````````````````````````````399.10检验试剂检查情形表````````````````````````````````````````````````````````` ```````````````````````````409.11质量监控点、监控内容、监控方法、监控频次表````````````````````` ````````411.概述1.1.利巴韦林注射液（1ml：100mg）常温状态下是无色的澄明液体，属抗病毒药，用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎。

XX注射液生产工艺验证方案药业有限公司小容量注射剂车间验证方案项目名称XX注射液生产工艺方案日期验证方案审批表验证进度打算XX注射液生产工艺验证方案名目验证方案审批表1. 验证目的适用范畴职责有关背景资料验证项目、评判方法及结果6．漏项与偏差7．批阅本验证方案，并确认验证结果8．验证总结9.SOP的修订10.再验证时刻11 证明1.验证目的按照《药品生产质量治理规范》的要求，为保证小容量注射剂产品生产过程的稳固性，保证产品的质量，需要对生产工艺进行工艺验证。

XX注射液工艺验证是用于证明在确定的环境、工艺和操作下，所生产的产品能有效地防止微生物污染，保证所生产产品达到可同意的合格标准。

我公司小容量注射剂车间生产线是在完成设备验证、公用系统验证的基础上，为了确认XX注射液工艺规程在生产线的适用性，并确定各关键工艺参数的有效性，通过该品种各工序三批的实际生产，来确定在新生产环境、设备，人员相对固定的条件下能恒定的生产出符合产品质量标准及中国药典标准的小容量注射剂产品。

2.验证范畴本验证方案适用于本公司小容量注射剂车间XX注射液的生产工艺验证，当上述条件改变时，应重新验证。

3. 职责3.1验证领导小组3.1.1负责验证方案会审3.1.2负责验证方案的批准3.1.3负责对验证方案修改稿的批准3.1.4负责验证报告审核、批准3.2 验证小组3.2.1 负责验证方案的起草和审核。

3.2.2 负责按验证方案对有关人员进行培训。

3.2.3 负责组织、和谐本验证方案的实施。

3.2.4 负责收集、整理和审核验证数据，起草验证报告（如方案执行有偏差，要完成OOS调查报告）。

3.3 生产车间3.3.1 负责验证方案的实施。

3.3.2 负责组织培训岗位操作人员。

3.4 生产部3.4.1协助验证方案的实施，提供必要的技术支持。

3.4.2验证用仪器、外表的校验。

3.5 质保部3.5.1负责验证方案的审核，确保验证工作按批准的方案执行。

技术标准本品为利巴韦林与葡萄糖制成的灭菌水溶液。

1 品名: 利巴韦林葡萄糖注射液2 剂型: 大容量注射剂3 规格: 100ml：利巴韦林0.2g与葡萄糖5g4 代码：Y3155 处方：5·1基准处方利巴韦林 2.0 g葡萄糖50.0 g注射用水至1000ml5·2 标准生产量：1200000 ml/批所用的原辅料及数量名称代码数量利巴韦林Y122 2.4 Kg葡萄糖Y101 60 Kg针用活性炭F101 480g注射用水F108 至1200000 ml6 生产工艺及操作要求：6·1 配制（C级、温度18~26℃、湿度45~65%）：本工序包括称量、浓配、稀配等。

6·1·1 称量：在备料间根据指令核对原辅料品名、规格、批号、生产厂家、数量，本厂检验报告单或合格证(绿色合格证)、递交单。

称量前校准天平、电子称并检查是否在效期内。

按处方要求进行原辅料的称量，填写物料标示卡附于容器内外各一张，注明品名、规格、批号、重量、日期和操作者。

经复核后填写称量记录。

剩余原辅料扎紧袋口，标明原辅料名称、批号、剩余量、使用人，放置于暂存架。

换品种清场时，将剩余料密封，贴上卡片，标明名称、规格、批号、数量、日期，退回脱包间，返至仓库。

6·1·2 浓配：取规定量葡萄糖在浓配间投入到放有适量注射用水(70~85℃)的SH-Ⅰ浓配罐（编号：SB5004-1）中，搅拌溶解，使成50％~60％的浓溶液，加入0.03％（g/ml,以稀配体积计）的针用活性炭，搅拌混匀，煮沸(100℃)30分钟，稍冷，用钛棒过滤器加压过滤，内循环10分钟，泵入稀配罐。

6·1·3 稀配：在稀配间向SH-Ⅰ稀配罐（编号：SB5004-2）中加注射用水至全量的约80%，加规定量利巴韦林，加0.01％（g/ml,以稀配体积计）的针用活性炭，补加注射用水至全量，搅拌、回流15分钟，测pH值（规定：5.5~6.0，若不符合规定用稀盐酸或1M氢氧化钠调整）、含量(利巴韦林为98.0%~101.0%、葡萄糖为99.5%~102.5%)符合规定后，降温至50~60℃，用钛棒过滤器和0.45μm的膜滤芯加压过滤，终端用0.45μm的膜滤芯过滤至灌装。

专利名称：一种注射用利巴韦林及其制备方法专利类型：发明专利
发明人：黄金龙,施存元,郑昆武
申请号：CN201510528945.5
申请日：20150825
公开号：CN105232477A
公开日：
20160113
专利内容由知识产权出版社提供
摘要：本发明涉及一种注射用利巴韦林的制备方法，注射用利巴韦林的制备原料包括利巴韦林、甘露醇，注射用水和药用炭；步骤如下：1）预先向配液罐中加入注射用水，再加入利巴韦林、甘露醇，然后用注射用水进行溶解，搅拌使其充分混匀；2）搅拌20~40分钟后，开启循环泵经钛棒过滤器打循环4~6分钟；3）将药液经循环管道的钛棒过滤器滤至分液器后进行灌装，并半加塞；4）上述的药液从配制到灌装结束≤10h，灌装后的中间产品应在1小时内进行冻干，5）压塞：冻干结束，在真空状态下压塞，搁板复位后对前后箱进行放空。

本发明的制备方法制得的利巴韦林注射液具有纯度高、产品稳定性好及药用效果好等优点。

申请人：浙江尖峰药业有限公司
地址：321000 浙江省金华市婺城区白汤下线高畈段58号X02幢办公质检楼二楼
国籍：CN
代理机构：杭州丰禾专利事务所有限公司
代理人：王从友
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