稳定性试验方案.doc

Stability Study Protocol
稳定性方案
Chloroquine Phosphate Tablets Protocol No.: PRO-ST-001-2008(1.2)
磷酸氯喹片 方案编号：PRO-ST-001-2008(1.2)

Stability Study Protocol for Exhibit Batch of
Chloroquine Phosphate Tablets USP, 250mg
规格为250 mg的USP磷酸氯喹片
长期、中期及加速稳定性研究方案

Project No.
项目号
DP-ST-001-2008

Prepared By: Date:
起草者： 日期：
Reviewed By QA: Date:
审核者： 日期：
Approved By: Date:
批准者： 日期：
Starting Date: Completed Date:
开始日期： 结束日期：

Stability Lab Page 8/ 9
稳定性实验室
Contents
目 录

1. Purpose目的…………………………………………………………………………………………1
2. Scope范围…………………………………………………………………………………………..1
3. References参考资料…………………………………………………………………………………..1
4. General Information基本信息………………………………………………………………………..1
4.1 Stability Samples稳定性研究样品…………………………………………………………1
4.2 Product Outline样品概述………………………………………………………………..……1
4.3 Formulation处方………………………………………………………………………………1
4.4 Container-Closure Systems包装……………………………………………………………1
4.5 Labeling标签…………………………………………………………………………………..1
4.6 Samples and Package样品与包装………………………………………………………….1
5. Stability Testing稳定性测试…………………………………………………………………………1
5.1 Sample Receipt and Storage样品接收与储存……………………………………………1
5.2 Storage Conditions and Testing Time Points储存条件与检测时间点……………………1
5.3 Sampling取样…………………………………………………………………………………1
5.4 Testing Matrix稳定性测试项目表……………………………………………………………1
5.5 Parameters and Acceptance Criteria检测项目及质量标准………………………………1
5.6 Degradation products降解产物……………………………………………………………1
6. Data Presentation数据汇总…………………………………………………………………………1
7. Reporting报告………………………………………………………………………………………1
7.1 Intermediate Reports中期报告………………………………………………………………1
7.2 Summary Report总结报告…………………………………………………………………1
7.3 Stability Documents稳定性文件夹…………………………………………………………1
8. Appendix附件…………………………………………………………………………………………1

1. Purpose
目的
The purpose of stability testing is to provide evidence of how the Quality, Strength, Degradation Products and Purity of the Chloroquine Phosphate Tablets USP, 250mg will change with time under the influence of environmental room temperature and relative humidity conditions. Data collected from the stability study will enable recommended storage conditions and provide justification for establishing and submitting the data to regulatory authorities for approving the shelf life for marketing purposes.
In addition, 3 months of the stability data will be submitted to US FDA as required for submission purposes of the ANDA application.

此稳定性研究的目的是为了考察磷酸氯喹片在环境因素的影响下(例如：温度和湿度)其性质、规格、降解产物和含量等随时间而变化的规律，依据稳定性研究的数据确定该产品的储藏条件和有效期。
2. Scope
范围
This procedure is applicable to Finished Product Stability Lab at Hisun Pharmaceutical (Hangzhou) Co. Ltd. Fuyang, Hangzhou.
适用于浙江台州海正药业成品药稳定性实验室。
3. References
参考资料
3.1 ICH Harmonized Triparties Guideline for Stability Testing of New Drug Substances and Drug Product 06, 2003. [ICH Q1A (R2)]
新原料药和新制剂的稳定性测试指南06, 2003. [ICH Q1A(R2)]
3.2 ASSAY METHOD VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP, API AND CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 500 mg. (ARD-VDR-FPTM025A)
磷酸氯喹原料药、250mg和500mg片的含量测定方法验证报告。
3.3 RELATED SUBSTANCES METHOD VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP, API AND CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 500 mg. (ARD-VDR-FPTM025B)
磷酸氯喹原料药、250mg和500mg片有关物质方法验证报告。
3.4 DISSOLUTION METHOD VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 500 mg. (ARD-VDR-FPTM025C)
磷酸氯喹250mg和500mg片溶出度方法验证报告。
4. General Information
基本信息
4.1 Stability Samples
稳定性样品
4.1.1 One Exhibit Batch for 250mg strength will be included in the stability study.
规格为250mg的磷酸氯喹片各一批。
4.1.2 One batch of 250mg reference product will also be placed on stability study.
规格为250mg和的磷酸氯喹对照制剂各一批。
4.2 Product Outline
样品信息
Batch No.
批号
Strength
规格(mg)
Package Size
包装规格
Batch Size
批量(Tablets)
Mfg. Date
生产日期
Pkg. Date
包装日期
Manufacturer
生产商

250
50 Tablets/ Bottle
360,,000

Hisun
海正
100 Tablets/ Bottle

500 Tablets/ Bottle

61924A
250
50 Tablets/ Bottle
NA
NA
NA
West-ward
4.3 Formulation
处方
4.3.1 The formulation of Chloroquine Phosphate USP Tablets, 250 mg, is as follows:
规格为250mg的USP磷酸氯喹片处方如下：Table 1. Formula and batch size
Batch size: 360,000 tablets ( 172.8 Kg )
成分
Ingredients
mg / 片
mg / tablet
Kg / 批
Kg / batch
Manufacturer
原料药API*
250
90
IPCA
微晶纤维素(102)
MCC (Type 102)
154
55.44
JRS
二水磷酸氢钙
Dibasic Calcium Phosphate Dihydrate
40
14.4
JRS
滑石粉Talc
24
8.64
Merck
胶体二氧化硅
Colloidal Silicon Dioxide (Aerosil 200)
4.8
1.728
Degussa
硬脂酸镁
Magnesium Stearate
7.2
2.592
Peter Greven
总量Total
480
172.8

4.4 不适用4Container-Closure Systems
包装
Packing Material
包材
Batch No.
批号
Packing Material Description
包材描述
Manufacturer
供应商
60 cc HDPE bottle
60 cc HDPE瓶
WE070601
Bottle: 60 cc opaque white HDPE round bottle
瓶：60cc白色不透明HDPE圆瓶
Cap: φ32 mm opaque white CRC cap, with induction sealing
盖：φ32mm白色不透明CRC圆盖，带内封
Triveni Polymers Pvt. Ltd (Bottle)
VBC Inc. (CRC Cap)
Tekniplex (Liner)
上海海昌
120 cc HDPE bottle
120 cc HDPE瓶
KQ080101
Bottle: 120 cc opaque white HDPE round bottle
瓶：120cc白色不透明HDPE圆瓶
Cap: φ36 mm opaque white CRC cap, with induction sealing
盖：φ36mm白色不透明CRC圆盖，带内封
Triveni Polymers Pvt. Ltd (Bottle)
VBC Inc. (CRC Cap)
Tekniplex (Liner)
上海海昌
450 cc HDPE bottle
450 cc HDPE瓶
WA080101
Bottle: 450 cc opaque white HDPE round bottle
瓶：450cc白色不透明HDPE圆瓶
Cap: φ58 mm opaque white CT cap, with induction sealing
盖：φ58mm白色不透明CT圆盖，带内封
Triveni Polymers Pvt. Ltd (Bottle and Cap)
Tekniplex (Liner)
上海海昌
4.5 Labeling
标签
The Product Name, Batch Number, Strength, Storage Condition, Package Type, No. and Stored by/ Store Date will be included on the label.
标签应包括品名、批号、规格、储存条件、包装类型、编号及储存人/日期。
FP Stability Lab
成品药稳定性实验室
Product Name品名：

Batch No./ Strength批号/规格：

Storage Condition储存条件：

Package type包装类型：

No.编号：

Stored By/ Date储存人/日期：
4.6 Samples and Package
样品与包装
The drug product for stability testing will be packaged in the same configuration as that for the marketing purposes.
稳定性研究样品与上市的包装要一致，同时药品的大包装也进行稳定性实验。
5. Stability Testing
稳定性试验
5.1 Sample Receipt and Storage
样品接收与储存
As soon as received from QA or Formulation Development Department, each batch of samples will be labeled and placed in storage chambers under the required conditions.
从QA部门或者制剂研发部门接收到样品，按规定条件贴好标签并储存。
Batch No.
批号
Strength规格
Package Size
包装规格
Storage Condition
储存条件
Sample Size
样品数量

250 mg
50 Tablets/ Bottle
100 Tablets/ Bottle
500 Tablets/ Bottle
25℃ ± 2℃/ 60% RH ± 5% RH
23 Bottles/ Package size
30℃ ± 2℃/ 65% RH ± 5% RH
15 Bottles/ Package size
40℃ ± 2℃/ 75% RH ± 5% RH
12 Bottles/ Package size

7011671
250 mg
50 Tablets/ Bottle
25℃ ± 2℃/ 60% RH ± 5% RH
2 Bottles
40℃ ± 2℃/ 75% RH ± 5% RH
1 Bottle
Note
注
1. RLD recommended storage condition as Store at 20-25℃ ( 68-77F) (Controlled Room Temperature) and Protect from light and moisture.
室温参照仓库温度要求，室温通常不超过30℃。
The reference product (RLD) will also be labeled and placed in storage chambers under the required conditions at the same time.
同时也将对照制剂（RLD）按规定条件贴好标签并储存。

5.2 Storage Conditions and Testing Time Points
储存条件和检测点
Study Type
稳定性类型
Storage Condition
储存条件
Period
周期
Time Points（months）2
时间点（月）
Long Term
长期
25℃ ± 2℃/ 60% RH ± 5% RH
24 Months
0, 3, 6, 9, 12, 18, 24
Intermediate1
中期
30℃ ± 2℃/ 65% RH ± 5% RH
12 Months
0, 3, 6, 9, 12
Accelerated
加速
40℃ ± 2℃/ 75% RH ± 5% RH
3 Months
0, 1, 2, 3

Note
注
1. Intermediate stability samples will be pulled and analyzed only if the ambient (long term) stability results falls outside of the set specifications.
当完成加速稳定性研究且无重大变化时，停止中期稳定性研究。
2. Reference samples will be pulled out and analysed according to SOP ARD-ST009.
对照样品依据SOP ARD-ST009取样检测。
5.3 Sampling
取样
Strength
规格
Package Size
包装规格
Storage Condition
储存条件
Sampling Size
取样量
250 mg
50 Tablets/ Bottle
100 Tablets/ Bottle*
500 Tablets/ Bottle
25℃ ± 2℃/ 60% RH ± 5% RH
1 Bottle
30℃ ± 2℃/ 65% RH ± 5% RH
40℃ ± 2℃/ 75% RH ± 5% RH
The additional samples packed in bottles will be destroyed according to related SOPs by supervisor of stability Lab or the appointed person after completing each time point test. And the samples packed in pail will be sealed again and stored in warehouse.
瓶装样品在每个检测点检验完毕后，样品如果有剩余，应交回给稳定性实验室主管或指定人员做销毁处理。桶装样品封好继续在仓库中储存。
Note
注
* Usually these samples are not used for testing, unless results on other conditions are not satisfactory or fail the specifications.
正常情况下不取样检测，除非客户有特殊要求。
5.4 Testing Matrix
稳定性测试项目表
Testing Matrix
测试项目表
Long-term Conditions
长期稳定性
Intermediate Conditions
中期稳定性
Accelerated Condition
加速稳定性
250 mg
50 Tablets/ Bottle
T
T
T
100 Tablets/ Bottle

500 Tablets/ Bottle
T
T
T
5.5 Parameters and Acceptance Criteria (to be revised as per specifications)
检测项目及质量标准 add Micro testing at time 0 and end of life
Items
检测项目
Method
方法
Specification
质量标准
Appearance
性状
ESS-GM026
250 mg
White uncoated tablets, round biconvex debossed ASC over 109 on one side, bisected on one side.
白色非包衣片，圆形两面凸的，片一面刻字“ASC 109”，另一面中间带有刻痕。

Water content*
水分
ESS-GM036
.
待定。
Dissolution
溶出度
ESS-STM-011C
Not less than 75%(Q) of the labeled amount in 45 minutes.
45分钟内溶出度不少于75%（Q）。
Assay
含量
ESS-STM-011A
Chloroquine Phosphate Tablets contain not less than 93.0 percent and not more than 107.0 percent of the labeled amount of C18H26ClN3·2H3PO4.
应为标示量的93.0%-107.0%。
Related substances/ degradation products
有关物质/降解产物
ESS-STM-011B
Individual unspecified impurity is NMT 0.10%.
单个未知杂质不得过0.10%。
Total impurity is NMT 1.0%.
总杂质不得过1.0%。
* It is only applicable to Chloroquine Phosphate Tablets, 500 mg.
仅适用于500mg磷酸氯喹片。
5.6 Related substances/ Degradation products
有关物质/降解产物
Maximum daily dose
最大日剂量
Reporting threshold
报告限
Identification threshold
鉴定限
Qualification threshold
界定限
1,000 mg
LOQ
0.2%
0.2%
6. Data Presentation
数据汇总
The stability data will be presented in the Stability Summary Report (see examples in Appendix B). Stability Summary Report will be completed for each storage condition of drug product placed on stability.
稳定性研究数据填写在稳定性研究汇总报告中（见附件B），按产品的储存条件分别填写附件B。
7. Reporting
报告
7.1 Intermediate Reports
中期报告
The stability laboratory will issue intermediate reports according to Appendix B within 30 days at each testing time points. The written explanation should be provided if test result is not reported within required time.
在检测点30天内对该检测点数据按附件B进行中期报告，如果没有按规定时间进行报告，必须有书面说明。
7.2 Summary Report
总结报告
On completion of the study, the stability laboratory will issue a report summary with signature and date according to appendix B.
在完成稳定性研究后，按照附件B进行总结报告。
7.3 Stability Documents
稳定性文件夹
The stability documents should include the following, but not limited to:
稳定性文件夹应该包括但不局限于以下内容：
● Name and description of drug product
品名及产品描述
● Manufacturer, batch No., batch size(s), mfg. date, package type and package date
产品生产厂商、批号、批量、生产日期、包装类型和包装日期
● Drug product strength
产品规格
● API manufacturer/supplier
API厂商
● Method validation reports
方法验证报告
● All analytical and physical data, including identity test, chemistry assay, physical test
所有检验数据，包括鉴别、含量及测试。
● Acceptance criteria
质量标准
● Where applicable, a description of statistical methodology applied, including parameters estimated, assumptions made, and model(s) used; transformations, calculations or operations performed on the data; an explanation and statement of the conclusions drawn from the statistical analysis relative to the objective(s) of the study; the name(s) of software employed in the statistical evaluations.
实验数据和结果所采用的分析方法、统计方法、转换计算、假设、采用模式及相应软件信息等，所得结论及相关说明。
● The numbers and titles of standard operating procedures applied
采用的Sop编号和标题
● A signed and dated statement of intermediate reports
中期报告
● The records of all samples, original data and testing reports
样品的原始数据和测试报告
● Requiring form for stability study
稳定性研究申请表
8. Appendix
附件
Appendix B1: STABILITY STUDY SUMMARY REPORT (Hisun products/ 250 mg)
附件B1：稳定性研究报告(海正产品/250mg)
Appendix B2: STABILITY STUDY SUMMARY REPORT (Brand)
附件B3：稳定性研究报告(Brand)