工艺验证草案
工艺验证草案
Process Validation Protocol A片剂100mg制造工艺验证
Process validation of Vermox 100mg Tablets
目录CONTENT TABLE
目录CONTENT TABLE (2)
1.背景介绍INTRODUCTION (4)
1.1验证产品基本信息BASIC INFORMATION OF VALIATIONED PRODUCT (4)
1.2背景Background (4)
1.3目的Purpose (4)
1.4范围Scope (5)
2.责任RESPONSIBILITY (7)
3.方法APPROACH (8)
3.1工艺验证与验证批释放Process validation and release of the validation batch (8)
3.2Comparison to biobatch (8)
3.3稳定性研究Stability study to this process validation (8)
3.4与工艺验证相关的清洁验证Cleaning validation related to this process validation (9)
3.5分析方法与IPC/释放标准Analytical method overview including IPC /release specifications (9)
3.6结果记录与评估的方法Methods for recording & evalusting results (9)
4.工艺介绍PROCESS (11)
4.1产品处方Product Formulation (11)
4.1.1 处方Formulation (11)
4.1.2 原材料合格供户清单Qualified suppliers List of raw materials (12)
4.2接触容器Immediate containers (13)
4.3生产设备和设施Manufacturing Equipment and Facility (13)
4.4工艺流程图Process Flow Diagram (14)
4.5关键工艺参数与变量Critical Process Parameters and Variables (15)
5工艺验证过程PROCESS VALIDATION (16)
5.1粘合液制备Prepare binding solution (16)
5.2干混工序Dry-mixing (Pre-mixing) (18)
5.3湿法制粒和干燥工序Wet Granulation and Drying (20)
5.4整粒工序Breaking (23)
5.5不加硬脂酸镁的混合Mixing without Magnesium stearate (24)
5.6加硬脂酸镁的混合Mixing with Magnesium stearate (26)
5.7中间体桶料In drums (30)
5.8压片工序The tableting process (32)
5.9贮存时间Holding time study (36)
6验证中偏差/变更处理DEVIATION AND CHANGE HANDLING (38)
7培训TRAINING (38)
8参考文献REFERENCE ........................................................................ 错误!未定义书签。
1. 背景介绍INTRODUCTION
1.1 BASIC INFORMATION OF VALIATIONED PRODUCT
产品名称PRODUCT NAME: A片剂
Vermox Tablets
物料编码
MATERIAL CODE:
剂量STRENGTH: 亚批次
SUB-BATCHES
标示重量NORMAL WEIGHT 批量
BATCH SIZE:
批记录编号BPR CODE 变更控制编号CCN:
本次验证工艺步骤
PRODUCTION STEP:
制粒/整粒/混合/压片Granulating/Breaking/Mixing/Compressing
1.2 Background
生产的A100mg口服片剂的主要成分是BBBB，自1988年投放到生产后，先后进行了三次工艺验证，详细情况参见下表。
次数No 时间
Time
报告号
Report code
验证内容
Content
结果
Results
1 合格Pass
2 合格Pass
3 合格Pass
自2001年验证完成后，A的生产工艺和生产设备均没有发生变更，未出现与工艺相关的不符合事件。依据中国cGMP第七章/第58条、工艺验证管理程序SMP-VMP006有关周期性再验证的规定，在2001年成功实施工艺验证后在2006年需要对A100mg口服片剂的制造工艺再次进行全面的验证，确保现行的工艺流程可以继续稳定、持续的生产出合格的产品。
1.3 Purpose
该方案的目的是The purpose of this protocol is to:
确认所需验证的工艺能够有效并重复地生产出符合所有事先确定的质量标准与品质的中间产品，并且如果适用的话，确认在制造完成后至包装开始前的预先设定的中间品保留时间能够始终一致地保证中间产品的质量特性。
提出一个工艺验证方案。该方案确定在实际操作条件下需要监控的关键工艺参数和变量，概括对中间品样品的取样与检测的要求，并规定工艺监控及产品检测的接受标准。
更具体而言，本次工艺再验证工作的目的是用书面证据来证明当运行操作正确时，A100mg口服片剂的生产工艺过程能够始终一致地生产出符合已确定的接受标准的产品。
1.4 Scope
本验证草案适用于A100mg片的制造工艺再验证，依据本次验证的目的，在本次验证中将要研究的工艺步骤如下：
No 工艺步骤
Process step 简述
Description
验证范围
Scope
1 筛粉
Sieving
将物料微晶纤维素101、微粉硅胶、BBBB和羧甲淀粉钠按顺序过筛并
收集于一步制粒机容器中。
Pass ingredients （Microcrystalline Cellulose 101, Colloidal
Anhydrous Silica, Mebendazole and Carboxymethylstarch Sodium）
through Sweco 800L into the container of WSG-UD-200
适用Applicable
不适用Not Applicable
2 制备粘合液
Binder solution
将糖精钠、日落黄、十二烷基硫酸钠（进口）加入中制成色液，同时制
成淀粉浆，将色液加入淀粉浆中搅拌均匀
适用Applicable
不适用Not Applicable
3 干混
Dry mixing
过筛后的物料在1/B/R01 混合均匀。关键参数包括阀控制压力、工作压
力、排风阀位置、进风温度和混合时间
Mix the materials from sieving to homogeneous with 1B/R01. critical
parameters include Control pressure of valves, Operating pressure,
Exhaust-air flap, Inlet-air temp. and Premixing time
适用Applicable
不适用Not Applicable
4 喷液
Spraying
利用喷液泵向混合后物料中喷入淀粉浆后再喷入已溶于2335ml异丙醇
的桔子香精和500ml的异丙醇。关键参数包括喷液压力、进风温度、排
风阀位置、喷嘴口径、喷嘴数目和泵速
Spray the solution into mixed material with spray pump. Then spray
the Flavour solution and isopropanal onto granules. critical parameters
include Spraying pressure, Inlet-air temp., Exhaust-air flap, Nozzle
diameter, Number of nozzles and Pump speed
适用Applicable
不适用Not Applicable
5 颗粒干燥
Drying
关键参数包括进风温度和产品温度
critical parameters include Inlet-air temp. and Product temp.
适用Applicable
不适用Not Applicable
7 整粒
Breaking
用整粒机将1/2亚批的物料整粒
Pass the 1/2 subbatch through 1/B/S02 & collect in the 1/B/R02-V2
用整粒机将物料微晶纤维素101、滑石粉与2/2亚批的物料整粒Check
and pass the materials （Microcrystalline cellulose 101 and Talc）&
2/2 subbatch through 1/B/S02 & collect in 1/B/R02-V2。
适用Applicable
不适用Not Applicable
8 加硬脂酸镁前混合
Blending without
Magnesium stearate
将收集到混合机的两个亚批物料进行混合。关键参数包括混合时间和转
速
Mixing the two subtach materials from breaking step. Critical
parameters include mxing time and speed.
适用Applicable
不适用Not Applicable
9 终混Final bleanding 使用20目不锈钢筛对硬脂酸镁进行手工过筛，然后加入到混合机中混
合均匀。关键参数包括混合时间和转速
Sieving the Magnesium stearate with S.S Sieve 20mesh and then add
适用Applicable
不适用Not Applicable
No 工艺步骤
Process step 简述
Description
验证范围
Scope it into mixing machine 1/B/R02-V2. Critical parameters include mxing
time and speed.
10 装桶
In drums
装桶储存
Filling in drums
适用Applicable
不适用Not Applicable
11 中间体贮存
Granula holding
在半成品库存放至压片工序开始
Storage in HFP warehourse till compression
适用Applicable
不适用Not Applicable
12 压片
Tableting
在压片机上用双凹冲将物料压成片子，直接装入带盖100L不锈钢桶中
The mixture is pressed to circular tablets by the tablet press machine
(1/C/K01, 1/C/K02) using biconcave punches. Transfer the tablets into
s.s. buckets with a cover.
适用Applicable
不适用Not Applicable
13 半成品贮存
Tablet holding
在半成品库存放至包装工序开始
Storage in HFP warehourse till packaging
适用Applicable
不适用Not Applicable
A片剂100mg的制造工艺参见生产批记录BPR2340 05，其中筛粉、制粒和整粒等工艺步骤为两个亚批分别进行生产，在混合阶段合为一个整批。
2. 责任RESPONSIBILITY
部门 Department
姓名 Name 职责 Responsibility
新产品与技术支持 NPI&TS
验证协调人Validation corrdinator
?
起草验证草案Draft protocol
?
负责验证数据的收集及数据分析Collect and analysis the validation results ? 负责对相关人员进行培训，确保验证工作按草案进行Train related person ?
协调进行验证中可能出现的偏差的调查、完成变更的书面记录、完成验证报告
Coordinate the deviation and change handling during validation, draft validation report
固体制造 Solid
车间协调人Corrdinator in workshop
?
负责安排具有资格的操作人员及IPC 人员开展验证工作Responsible for arranging qualified operator and IPC tester
? 负责设备的清洁、安装、生产等工作并提供原始记录Responsible for equipment cleaning, installing, manufacturing and data recording ? 负责向验证管理小组及时报告验证中出现的问题Report timely discrepency observed during validation to Validation Team
?
协助验证协调人完成验证报告Assist to finish validation report
?
车间操作人员负责按照草案设计的要求执行验证，验证中观察到的实际工艺参数和变量记录在批记录中完成。The process validation are exectued by the operators strictly based on the approved protocol. The process parameters and variables should be recored in Batch Production Record by operators.
?
IPC 检查由IPC 检验人员完成，同时将检验结果填写在批记录或本草案设计的附件记录表中，在检验过程中产生的任何打印记录须附在相应的记录表中。The IPC test should be performed by IPC operators. The results will be recorded in the Batch Production Record or annexed forms designed in this protocol, together with any print-out during test. ?
QC 负责完成验证中规定的检验项，同时将检验过程和结果记录在相应的检验记录和本草案设计的附件记录表中，在检验过程中目产生的任何打印记录须附在相应的记录表中。The predefined test items for QC will be performed in QC laboratories. The results will be recorded in the related Test Record or annexed forms designed in this protocol, together with any print-out during test.
?
QA 负责验证现场执行的监控QA is responsible for site supervision of validation implementation
固体制造Solid
验证管理小组Validation management team
?
负责验证草案及报告的审核及批准Review and approval of the project documents concerning contents, correctness, completeness
?
负责对验证中出现的问题提出指导意见、执行偏差调查、批准变更等Coach the investigation for observations and approve the change during validtaion
新产品与技术支持 NPI&TS
质量控制 QC
质量保证 QA
验证处 V&Q
质量认证部Q&C
?
负责验证草案及报告的批准Approval of the project documents concerning contents, correctness, completeness
?
负责对验证中出现的问题提出指导意见、执行偏差调查、批准变更等Coach the investigation for observations and approve the change during validtaion
3. 方法APPROACH
3.1 Process validation and release of the validation batch
此次验证为同步验证。采用供应商提供3批共计300kg的BBBB进行生产。本次验证中变更的物料及使用的入库序号参见下表。
参考文件
Reference Document
原辅料名称
Raw Material Name
物料编号
Material Number
入库序号Lot number
第一批
For first batch
第二批
For second batch
第三批
For third batch
各物料的生产商和供应商参见4.1.2节the information about manufacturer and vendor see section 4.1.2
本次工艺验证应该进行3个连续而且成功的批次。验证批为正常生产批量300kg/批。
验证批产品必须经过验证测试结果分析，符合释放要求，且验证报告被批准后，才可以释放。
由于本次验证为同步验证，没有对处方、工艺步骤、工艺参数、生产设备等进行变更，因此对于每个验证批的产品可以在测试结果合格、经过分析符合释放要求的前提下，形成中间报告支持释放。
3.2 Comparison to biobatch
由于本产品已经上市多年(始于1990年)，所以不涉及。
3.3 Stability study to this process validation
依据稳定性考察程序制订稳定性考察方案，结果仅用于公司内部质量控制。由于本次验证没有进行任何影响产品生产和质量的变更，同时每年均对首批生产的该产品进行稳定性考察，因此本次验证不涉及验证批的稳定性研究。
3.4 Cleaning validation related to this process validation 参见
4.3节“生产设备与设施”项。
See section 4.3, Manufacturing Equipment and Facility.
3.5 IPC/Analytical method overview including IPC /release
specifications
方法/标准列表List of test method and specification
程序号Procedure code 对象
Objects
方法类别
Type of Test Method
标准类别
Type of specification
方法验证列表List of test method validation
文件编号Document Code 验证方法名称Validation Name 验证时间Year
3.6 Methods for recording & evalusting results
草案设计的记录单、批记录和检验记录的填写主要涉及内容为工艺参数和变量的记录、IPC检验记录以及QC检验记录，所有这些记录的填写必须符合XJP质量记录管理程序SMP-
DCP003的要求。
验证协调人负责收集整理批记录、IPC检验结果和QC检验结果。将结果进行汇总、统计和科学分析，并与上一次验证结果进行比较后完成验证结果评估，总结验证结论。
4. 工艺介绍PROCESS
4.1 Product Formulation
4.1.1 处方Formulation
下表列出在A片剂100mg生产时产品的处方。
Table below presents the product formulation used for the manufacture of Vermox tablet 100mg.
参考文件
Reference Document:Master Formula No. (QA
Authoritation number) F84
批量
Batch Size:
物料编号Material Number
原辅料名称
Raw Material Name
每批的数量
Quantity per Batch
亚批次
Sub.batch
010193
备注COMMENTS: NA
4.1.2 原材料合格供户清单Qualified suppliers List of raw materials
下表列出了在工艺验证批次中将要使用的所有物料合格供户。
Table below lists the qualified suppliers of all the materials to be used in the process validation batches.
参考文件
Reference Document 进口合格供户Xian Janssen Import Qualified Suppliers List (2005.11.15) 国内合格供户Xian Janssen Local Qualified Suppliers List (2005.11.15)
原辅料名称
Raw Material Name
物料编号
Material Number
生产商
Manufacturer
供应商
Vendor
如果对于某个给定的原辅料所列的制造商或供应商多于一个时，请注明在执行该验证时所使用的该物料的制造商或供应商。If more than one manufacturer or supplier is listed for a given raw material, please indicate which manufacturer or supplier’s material will be used in the execution of this PQ.
依据RATIONALE: （如果对于给定的物料，其生产商或供应商多于一个）。(If more than one manufacturer or supplier is listed for a given raw material ) NA
备注COMMENTS:
NA
4.2 Immediate containers
阶段Phase 接触容器Immediate containers
制造阶段与产品直接接触的设备Contact equipments in the manufacturing process 筛粉机、一步制粒机、整粒机、混合机和压片机与产品接触部分：304不锈钢Contact parts of Sieving machine, Fluid bed granulator, Breaking machine, Mixing machine and Compression machine: 304 stainless steel
颗粒、片子贮存的容器Containers for
granula and tablets
不锈钢桶SS bucket
内包装材料（国内销售）Primary
packaging material (Local)
PVC硬片、铝箔Foil PVC and Alu. Foil
内包装材料（国外销售）Pramery
packaging material (Export)
黑色塑料袋 Black plastic bag
4.3 Manufacturing Equipment and Facility
根据制造A片剂100mg的现行版批记录BF2340 05在检查表1中列出了在工艺验证批次中将使用的所有生产设备。
用于A100mg片制造的主要生产设备必须完成设备验证、处于校验有效期内；相应的清洁程序的验证状态须进行回顾或评估。具体的检查结果参见检查表1。
与A片剂100mg制造相关的设施与公用系统均得到验证，可用于生产。
4.4 Process Flow Diagram
4.5 Critical Process Parameters and Variables
下表列出所有关键工艺参数和关键工艺变量。关键工艺参数必须设定在特定的设定点或范围内，而关键工艺变量则必须控制和维持在特定的目标或范围内。
工艺阶段Process Stage
关键的工艺参数与变量
Critical Process
Parameters and Variable
批记录步骤编
BPR Step
Number
参数设定值/目标值（范围）
Parameter
Set point / Variable Target (Range)
流化床制粒Granulation with Fluid bed granulator
干混Pre-Mixing 阀控制压力Control pressure of valves 3 1.45bar 工作压力Operating pressure 3 6bar 排风阀位置Exhaust-air flap 3 38-48% 进风温度Inlet-air temp. 3 50-60℃混合时间Premixing time 3 2-4min
制粒Granulation 喷液压力Spraying pressure 4 3.5bar
进风温度Inlet-air temp 4 55- 60℃排风阀位置Exhaust-air flap 4 38-48% 喷嘴口径Nozzle diameter 4 3mm
喷嘴数目Number of nozzles 4 6
泵速Pump speed 4 155-175rpm
颗粒干燥 Drying 进风温度 Inlet-air temp. 5 75-85℃混合Blending
不加硬脂酸镁的混合Mixing without Magnesium stearate 混合时间Mixing time 7a 20min. 转速Speed 7a 1
加硬脂酸镁的混合
Mixing with Magnesium stearate 混合时间Mixing time 7c 10min. 转速Speed 7c 1
压片Tableting
压片Tableting 压片机速度Speed9120,000 ~ 150,000 tablets / hr. 片重Weight 9 300±7.5 mg
冲头直径Punch diameter 910.0mm
冲头标记Inscription 9
上冲 upper punch
下冲 lower punch
Me
100
5 工艺验证过程PROCESS VALIDATION 5.1 Prepare binding solution
工艺步骤Process step 主要设备
Critical Equipment
批记录对应步骤
Reference
制备粘合液
Prepare binding solution 200L配液罐
变速搅拌器
Step 2 in BF2340 05
5.1.1 Objective and critical parameters
证明使用糖精钠、日落黄、十二烷基硫酸钠（进口）和淀粉搅拌能够持续及重复地制备出符合要求的粘合液。
To demonstrate that the manufacturing process for using Saccharin Sodium, Sunset yellow, Sodium lauryl sulfate and starch to produce consistently and reproducibly binder solution
观察粘合液并进行粘度测试。粘合液无泡沫和可见团块，粘度仅作为参考。
Observe the paste and check the viscosity. The paste should be foamless and no lumps should be
visible. The viscosity of paste is for information only.
关键参数
Critical parameters: a. 搅拌速度mixing speed
b. 搅拌时间mixing time
c. 在线匀化时间homogenizing time by in-line mixer
5.1.2 Sampling plan
取样时间：喷液前
Time of sampling: before spraying
取样位置：容器的上下部的中央位置
Place of sampling: the middle of top and bottom in the container.
取样量：每个样品50ml
Sampling size: about 50 ml each.
5.1.3 Test plan
喷液前取样置于透明容器中目测
Visual aspect immediately before spraying (in a clear transparent recipient)
喷液前取样50ml置于容器中进行温度测试
Perform a temperature measurement before spraying (about 50ml in recipient)
进行粘度测试
Perform a viscosity measurement. Refer to Tylenol binding solution test method
5.1.4 Acceptance citeria
无团块、不溶性颗粒和泡沫
No lumps and insoluble particles should be visible and the solution should be foamless.
温度结果留存供参考
工艺步骤Process step 主要设备
Critical Equipment
批记录对应步骤
Reference
制备粘合液
Prepare binding solution 200L配液罐
变速搅拌器
Step 2 in BF2340 05
The temperature of the paste is for information only.
粘度结果留存供参考
The viscosity of the paste is for information only.
5.1.5 Results recording
监控事先确定的制造工艺参数及变量并将观察结果、建议和测试结果记录在结果附件Script1中
Monitor and record the pre-defined manufacturing process parameters and variables, then record
process observation results, the comments of process obrvation and test resluts are recorded in Script1
5.2 Dry-mixing (Pre-mixing)
工艺步骤Process step 主要设备
Critical Equipment
批记录对应步骤
Reference
干混工序
Dry-mixing (Pre-mixing) 一步制粒机
Granulation machine, 1/B/R01
Step 3 in BF2340 05
5.2.1 Objective and critical parameters
证明按规定的加料次序将API等物料加入一步制粒机，经一步制粒机一步完成预混，能够持续稳定的制备出符合所有相关产品质量标准的颗粒。
To demonstrate that under the stated material feeding process (including API), the manufacturing
process for using granulator that could complete pre-mix process step and could consistently and
reproducibly produce a granule that compiles with all relevant product specifications.
在完成预混工序后由容器中部取样进行粒度。测试结果仅供参考。
To determine the particle size distribution of the sample taken from the middle of the vessel with a
sampling thief after pre-mixing. Test is performed only for information.
关键参数
Critical parameters: a. 阀控制压力Control pressure of valves
b. 工作压力Operating pressure
b. 排风阀位置Exhaust-air flap
c. 进风温度Inlet-air temp.
d. 混合时间Premixing time
5.2.2 Sampling plan
5.2.2.1 粒度分布Particle size distribution
取样位置：容器中部
Place of sampling: in the middle of the container
取样量：>100 g
Sampling size: >100 g
5.2.3 Test plan
5.2.3.1 粒度分布Particle size distribution
仪器Apparatus: Fritsch analysette 3 (1/F/L 03) with sieve-size: 1000um, 850um, 500um, 250um,
150um, 75um and bottom
方法Method: Vibration time: 5 minutes, vibration height: 1.5 mm
5.2.4 Acceptance citeria
5.2.4.1 粒度分布Particle size distribution
信息留存供参考 For information only
工艺步骤Process step 主要设备
Critical Equipment
批记录对应步骤
Reference
干混工序
Dry-mixing (Pre-mixing) 一步制粒机
Granulation machine, 1/B/R01
Step 3 in BF2340 05
5.2.5 Results recording
监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script2.1中
Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 2.1
5.3 Wet Granulation and Drying
工艺步骤Process step 主要设备
Critical Equipment
批记录对应步骤
Reference
湿法制粒和干燥工序
Wet Granulation and Drying 一步制粒机
Granulation machine, 1/B/R01
Step 4/5 in BF2340 05
5.3.1 Objective and critical parameters
证明按规定的加料次序将物料加入一步制粒机，经一步制粒机一步完成混合、制粒、干燥的工序能够持续稳定的制备出符合所有相关产品质量标准的颗粒。
To demonstrate that under the stated material feeding process, the manufacturing process for using
granulator that could complete pre-mix, granulation & granule dry process steps and could consistently and reproducibly produce a granule that compiles with all relevant product specifications.
在完成干燥工序后由容器中部取样进行粒度和干燥失重测试，同时进行含量均匀性分析。测试结果仅供参考。
To determine the particle size distribution, and LOD of the sample taken from the middle of the vessel and content uniformity with a sampling thief after drying. Test is performed only for information.
关键参数
Critical parameters: a. 喷液速率spray rate
b. 喷嘴口径Nozzle diameter
b. 喷液时间spraying time
c. 产品温度product temperature
d. 干燥时间drying time
5.3.2 Sampling plan
5.3.2.1 粒度分布Particle size distribution
取样位置：容器中部
Place of sampling: in the middle of the container
取样量：>100 g
Sampling size: >100 g
5.3.2.2 干燥失重Loss on drying
取样位置：容器中部
Place of sampling: in the middle of the container
取样量：10 g
Sampling size: 10 g
5.3.2.3 含量均匀性Content homogeinity
取样位置：参见图5-1
Place of sampling: see figure 5 - 1.
取样量：每个样约150mg（1-3倍剂量），每个位置取三份样
Sampling size: about 150mg (1~3 times unit dose) in triplicate for each location.
(备注：因为当前的取样器对A中间体最多只能取样150~160mg，虽然取样量低于A片的单剂量，但参考QC检验方法的使用
量，可得出对该步验证目的无影响的结论。
Remarks: present unit dose only can sampling 150-160mg vermox intermediate. Alough the sampling weight is less than the
tablet unit, refers to QC testing method, we can draw the conclusion that 150-160mg sampling do no impact on validation