利巴韦林工艺验证

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``````````````````````````````````````````````````````````````````````````````````````````````````````````4

1.3.生产工艺流``````````````````````````````````````````````````````````````````````````````````````````````````````````5`

2.验证目的````````````````````````````````````````````````````````````````````````````````````````````````````````````````````5

3.验证的范围```````````````````````````````````````````````````````````````````````````````````````````````````````````````6

4.验证各部门职责及组织结构```````````````````````````````````````````````````````````````````````````````6

5.验证准备````````````````````````````````````````````````````````````````````````````````````````````````````````````````````7

6.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```````````````````````````````````````````````````````````````````````````````````````````````````````````20 6.5.灯检工序```````````````````````````````````````````````````````````````````````````````````````````````````````````24 6.6.包装工序```````````````````````````````````````````````````````````````````````````````````````````````````````````26

6.7.成品检验结果``````````````````````````````````````````````````````````````````````````````````````````````````28

7.偏差分析``````````````````````````````````````````````````````````````````````````````````````````````````````````````````29

8.验证结论``````````````````````````````````````````````````````````````````````````````````````````````````````````````````29

9.附表````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````29 9.1. 设备一览表及生产能力```````````````````````````````````````````````````````````````````````````````30 9.2.设备性能验证确认及检查情况表```````````````````````````````````````````````````````````````31 9.3参加验证人员培训情况检查表````````````````````````````````````````````````````````````````````32 9.4.厂房与公用设施验证的确认和检查情况表`````````````````````````````````````````````34 9.5.空气净化系统、工艺用水系统验证的确认和检查情况表`````````````````35 9.6.计量器具检查情况表```````````````````````````````````````````````````````````````````````````````````````36 9.7.三批（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`````````````````````````````````````````````````````````````````````````````37 9.8.质量检验系统验证和准备情况表```````````````````````````````````````````````````````````````38 9.9.检验仪器检查情况表``````````````````````````````````````````````````````````````````````````````````````39 9.10检验试剂检查情况表````````````````````````````````````````````````````````````````````````````````````40 9.11质量监控点、监控内容、监控方法、监控频次表`````````````````````````````41

1.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。

1.2.利巴韦林注射液组方较为简单，具体工艺处方如下：

处方：

物料名称 1ml：100 mg

利巴韦林 1000g

氯化钠 87g

药用炭 20g

共制成 10000支

处方依据：

中国药典2010年版二部

批准文号：国药准字H19999232

批准机构：国家药品监督管理局

1.3.生产工艺流程：

该产品从2010年批准生产以来，处方和生产工艺没有发生变更，产品质量基本稳定，没有质量事故发生。2012年公司搬迁和GMP改造，厂房设施发生了变更，精滤、稀配制、灌封等工序的生产环境由原来万级洁净区变更为现在的A级洁净区，生产操作人员在原来知识的基础上按照新版GMP进行再次培训，无论从操作技术还是生产理念都有很大的提高。

2.验证目的

根据2010版GMP要求，通过对利巴韦林注射液(1ml：100mg)产品工艺的验证，判断生产系统各要素和生产过程中可能影响产品质量的各种工艺变化因素，对其整个生产过程进行验证，以保证在正常的生产条件下，生产出合格、均一、稳定的利巴韦林注射液。同

时确定岗位SOP修订的合理性，分析影响产品质量的关键因素，纠正偏差，建立生产全过

程的运行标准和监控标准，确保产品质量安全有效。

3.验证的范围

本次验证是在该产品正常生产所需的厂房设施、生产设备、仪器仪表、检验设施设备及检验方法均经过了验证和校验、参与验证的相关人员都经过培训的前提下，按照批准的生产工艺规程和岗位SOP进行严格监控下的正常生产；所有记录真实、准确；所有抽样检

验严格按照批准的规程进行。当上述条件之一改变时，应重新验证。

4.验证各部门职责及组织机构

4.1验证组

4.1.1负责验证方案的审批。

4.1.2负责验证的协调工作，以保证本验证方案规定项目顺利实施。

4.1.3负责验证数据及结果的审核。

4.1.4负责验证报告的审批。

4.1.5负责发放验证报告证书。

4.1.6负责再验证周期的确认。

4.2设备动力部

4.2.1负责组织试验所需仪器、设备的验证。

4.2.2负责仪器、仪表、量器等的校正。

4.2.3负责设备的维护保养。

4.3质保部

4.3.1负责制定质量标准和检验操作规程。

4.3.2负责制定取样方案并取样对样品进行检验。

4.3.3负责起草验证方案。

4.3.4负责收集各项验证、试验记录，并对试验结果进行分析后，起草验证告，报验证委

员会。

4.4生产组织部

4.4.1负责拟定验证方案。

4.4.2负责验证方案的实施。

4.4.3负责设备操作。

4.5验证过程应严格按照本方案规定的内容进行，若因特殊原因确需变更时，应

填写验证方案变更申请书，报验证组批准。

5.验证准备

5.1设备

生产利巴韦林注射液(1ml：100mg)所用设备见附表1，所列设备均已通过验证和再验证见附表2。

5.2.人员

参加验证人员必须经过培训，培训结果及有关文件见附表3。

.

6.验证实施

按照确定的原辅料、包装材料、生产设备、检验仪器和试剂，由各验证小组按照验证方案，连续投料三批，每批**万支，进行生产工艺验证。

6.1.洗瓶工序

6.1.1.因素分析

本工序主要控制参数有：

a.洗瓶用水水温；

b.注水机注满水率；

c.甩水机甩净水率；

d.终端精洗用水的可见异物；

e. 远红外隧道烘箱的灭菌温度和灭菌时间。

以上因素中，甩水机甩水效果、注水机注满水率、终端精洗用水的可见异物检查等控制标准生产一直沿用，未做过修订；洗瓶用水水温、远红外隧道烘箱的灭菌温度与灭菌时间等参数因没有明确数据范围，表述不科学。在************GMP管理工作中，进行了如下修订。

6.1.2.验证记录：

洗瓶工序监控项目及监控结果1：

第9 页共42 页

洗瓶工序监控项目及监控结果2：

第10 页共42 页

洗瓶工序洗瓶效果评价结果

第11 页共42 页

6.1.3.结果评价

根据监控结果和检测结果判断参数标准的可控性与稳定性，分析是否存在偏差。

6.2.配制工序

6.2.1.因素分析

本工序主要控制参数有：

a. 浓配加水量；

b. 配制时注射用水温度；

c. 投料顺序

d. pH值调节范围

e.炭吸附时间

f. 药液搅拌时间 g．使用前后终端过滤器完整性检查以上因素中，首次加水量、配制时注射用水温度、投料顺序、pH值调节范围、炭吸附时间、使用前后终端过滤器完整性检查等控制标准生产一直沿用，未做过修订；药液搅拌时间参数因没有明确数据范围，表述不科学，在实施以品种为单元的GMP管理工作中进行了修订。另在制定本次利巴韦林注射液工艺验证方案时，我们对2012年1～6月份***批利巴韦林注射液半成品及成品检验结果数据的回顾性分析，半成品含量平均为****%、RSD 值为****%；成品含量平均为****%、RSD值为****%；半成品、成品含量相对稳定；pH值范围在5.0～5.5的占***%，且pH值灭菌后平均下降***；呈下降趋势。现利巴韦林注射液半成品pH值参数范围为4.5～5.5，拟将pH值参数范围调整为*****。修订的参数及标准如下。

6.2.2.验证记录

配制工序监控项目及监控结果

产品工艺验证利巴韦林注射液（1ml：100mg）

配制工序半成品质量评价结果

第14 页共42 页

产品工艺验证利巴韦林注射液（1ml：100mg）

6.2.3.结果评价

根据监控结果和检测结果判断参数标准的可控性与稳定性，分析是否存在偏差。6.3.灌封工序

6.3.1.因素分析

灌封本工序主要控制参数有：

a. 灌封前可见异物；

b. 灌封期间可见异物；

c. 灌装量；

d.灌封收率

以上参数中，灌封前可见异物、灌装量和灌封收率等控制标准生产一直沿用，未做过修订；灌封期间可见异物检查标准曾发生过两次变更，一次是05年因国家标准改变，将灌封期间可见异物检查的不合格率控制标准由**%变更为**%；另一次是11年企业为有效控制可见异物质量问题，结合*******的GMP管理工作，将灌封期间可见异物检查的不合格率控制标准由***%变更为**%。另因为利巴韦林注射液灭菌条件为110℃、30分钟，值远小于8，为确保灭菌后产品无菌合格，拟增加生产过程中的环境洁净度成品的细菌F

内毒素、微生物限度等为特殊监控指标。

6.3.2.验证记录

产品工艺验证利巴韦林注射液（1ml：100mg）

灌封工序监控项目及监控结果

第16 页共42 页

北南附表1：灌封期间可见异物结果

附表2：细菌内毒素、微生物限度检查结果

附表3：灌封室尘埃粒子检测结果( 批)

灌封室沉降菌检测结果( 批)

装量检查结果产品批号：

6.3.3.结果评价

根据监控结果和检测结果判断参数标准的可控性与稳定性，分析是否存在偏差。6.4.灭菌工序

6.4.1.因素分析

本工序主要控制参数有：

a. 设定灭菌温度、

b. 设定灭菌时间、

c. 预热时间、

d. 最大载量、

e. 装载方式

以上参数，灭菌温度、灭菌时间为批准的工艺参数；预热时间、最大载量、装载方式为经验总结，生产一直沿用，未做过修订。在实施以品种为单元的GMP管理工作中，通过自查发现，因灭菌过程中灭菌柜存在相对的冷点和热点，冷点影响产品灭菌效果，热点影响产品理化性质，而现检验用样品的取样方法多为随机取样，可能存在质量隐患。本次验证一方面欲通过对灭菌工序主要控制参数的监控，判断参数标准的可控性，另一方面增加冷点处产品的无菌检查，增加产品冷点和热点处理化性质的对比检查，以分析灭菌过程对产品质量的影响，判断是否需修订检验用样品的取样规程。

6.4.2.验证记录