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[21A] SOLID QUALITY STANDARD [21A] SOLID STP
  Prepared by   Same technique   date   Department of the development department
  Review Unit QC   Production Department
  Reviewed by   We 303 3 303 3 303∼3303 \sim 3   Shed
  Reviewed Date 2023. 11.21 s.1,
  Approved by   Chen Huoxiao   Approved Date 2023.1127
  Effective Date   December 01, 2023   Review before   November 30, 2026
  Distribution   QA, QC, Production Department, Warehouse
[21A]固体质量标准[21A]SOLID STP 制定人Prepared by 同技 年月日 制定部门Department 审核部门Review Unit QC 生产部 审核人Reviewed by 我们 303∼3 棚正 审核日期Reviewed Date 2023. 11.21 s.1, 批准人Approved by 陈火頨 批准日期 Approved Date 2023.1127 生效日期Effective Date 2023年12月01日 再审阅日期Review before 2026年11月30日 分发部门Distribution QA,QC,生产部,仓库 | [21A]固体质量标准[21A]SOLID STP | | | | | :---: | :---: | :---: | :---: | | 制定人Prepared by | 同技 | 年月日 | 制定部门Department | | 审核部门Review Unit | | QC | 生产部 | | 审核人Reviewed by | 我们 | $303 \sim 3$ | 棚正 | | 审核日期Reviewed Date | 2023. 11.21 | | s.1, | | 批准人Approved by | 陈火頨 | 批准日期 Approved Date | 2023.1127 | | 生效日期Effective Date | 2023年12月01日 | 再审阅日期Review before | 2026年11月30日 | | 分发部门Distribution | QA,QC,生产部,仓库 | | |

[21A] SOLID QUALITY STANDARD [21A] SOLID STP
  PROJECT TESTS
QUALIFIED SPECIFICATIONS
  appearance   Yellowish-white to white crystalline powder
  Differential   The peak time of the main peak should be consistent with that of the standard
  Content (HPLC) 98 % 98 % >= 98%\geqslant 98 \%
  moisture content 0.5 % 0.5 % <= 0.5%\leqslant 0.5 \%
  o-ethylphenylhydrazine hydrochloride 0.3 % 0.3 % <= 0.3%\leqslant 0.3 \%
  Phenylhydrazine hydrochloride 0.2 % 0.2 % <= 0.2%\leqslant 0.2 \%
  O-methylphenylhydrazine hydrochloride 0.2 % 0.2 % <= 0.2%\leqslant 0.2 \%
  Tryptonol 0.5 % 0.5 % <= 0.5%\leqslant 0.5 \%
  O-ethylaniline 0.3 % 0.3 % <= 0.3%\leqslant 0.3 \%
  7-Methyltryptonol 0.1 % 0.1 % <= 0.1%\leqslant 0.1 \%
  Any single impurity 0.50 % 0.50 % <= 0.50%\leqslant 0.50 \%
  Total impurities 1.0 % 1.0 % <= 1.0%\leqslant 1.0 \%
[21A]固体质量标准[21A]SOLID STP 项目TESTS 合格的标准QUALIFIED SPECIFICATIONS 外观 黄白色至白色晶体粉末 鉴别 主峰出峰时间应与标准品一致 含量(HPLC) >= 98% 水分 <= 0.5% 邻乙基苯肼盐酸盐 <= 0.3% 苯肼盐酸盐 <= 0.2% 邻甲基苯肼盐酸盐 <= 0.2% 色醇 <= 0.5% 邻乙基苯胺 <= 0.3% 7 -甲基色醇 <= 0.1% 任何单一杂质 <= 0.50% 总杂质 <= 1.0% 苼 | [21A]固体质量标准[21A]SOLID STP | | | :---: | :---: | | 项目TESTS | 合格的标准QUALIFIED SPECIFICATIONS | | 外观 | 黄白色至白色晶体粉末 | | 鉴别 | 主峰出峰时间应与标准品一致 | | 含量(HPLC) | $\geqslant 98 \%$ | | 水分 | $\leqslant 0.5 \%$ | | 邻乙基苯肼盐酸盐 | $\leqslant 0.3 \%$ | | 苯肼盐酸盐 | $\leqslant 0.2 \%$ | | 邻甲基苯肼盐酸盐 | $\leqslant 0.2 \%$ | | 色醇 | $\leqslant 0.5 \%$ | | 邻乙基苯胺 | $\leqslant 0.3 \%$ | | 7 -甲基色醇 | $\leqslant 0.1 \%$ | | 任何单一杂质 | $\leqslant 0.50 \%$ | | 总杂质 | $\leqslant 1.0 \%$ | | 苼 | |
  Storage conditions   Store tightly sealed
  Standard basis   Frugal inspection of the operating procedure number
  standard
CMC-SOP-QC-003-47
  The name of the prospective supplier   See the list of approved suppliers
  Sample size   Approximately 50 g
  Dress for sampling   Wear work clothes, hard hats, masks, gloves
  Analyze the dosage   About 10g
  Retest period   6 months
  The items to be tested during the re-inspection are required   Full inspection
储藏条件 密闭保存 标准依据 俭验操作规程编号 标准 CMC-SOP-QC-003-47 准的供应商名称 见经批准的供应商名录 取样量 约50g 取样时着装 穿工作服,戴安全帽,口罩,手套 分析用量 约10g 复验期 6 个月 复验时需检测项目 全检| 储藏条件 | | 密闭保存 | | :---: | :---: | :---: | | 标准依据 | | 俭验操作规程编号 | | 标准 | | | | | CMC-SOP-QC-003-47 | | | | 准的供应商名称 | 见经批准的供应商名录 | | | 取样量 | 约50g | | | 取样时着装 | 穿工作服,戴安全帽,口罩,手套 | | | 分析用量 | 约10g | | | 复验期 | 6 个月 | | | 复验时需检测项目 | 全检 |
  REVISION HISTORY

File encoding Issue No.
文件编码 Issue No.| 文件编码 | | :---: | | Issue No. |

Effective Date Effective Date
生效日期 Effective Date| 生效日期 | | :---: | | Effective Date |

Reason and content of the change Revised Detai1s
变更原因及内容 Revised Detai1s| 变更原因及内容 | | :---: | | Revised Detai1s |
CMC-STP-QA-003-48-00 2012.4 .9   New
变更历史REVISION HISTORY "文件编码 Issue No." "生效日期 Effective Date" "变更原因及内容 Revised Detai1s" CMC-STP-QA-003-48-00 2012.4 .9 新增 | 变更历史REVISION HISTORY | | | | | :---: | :---: | :---: | :---: | | 文件编码 <br> Issue No. | 生效日期 <br> Effective Date | 变更原因及内容 <br> Revised Detai1s | | | CMC-STP-QA-003-48-00 | 2012.4 .9 | 新增 | |

[21A] Standard Operating Procedures for Solid Inspection [21A] SOP for Solids
  Prepared by   January 27, 2023   Development of Sector D partment   Quality Department
  Review Unit QA QC
  Reviewed by   Everybody   This level of abundance
  Reviewed Date 2023. 11.27
  Approved by   Chen, Ya   Approved Date 2023 1127 2023 1127 2023^(')11272023^{\prime} 1127
  Effective Date   December 01, 2023   Review before   November 30, 2026
  Distribution QA,QC
[21A]固体检验标准操作规程 [21A]固体SOP 制定人Prepared by 包 2023年1月27日 制定部门D partment 质量部 审核部门Review Unit QA QC 审核人Reviewed by 每们 这级丰 审核日期Reviewed Date 2023. 11.27 批准人Approved by 陈,䞍 批准日期Approved Date 2023^(')1127 生效日期Effective Date 2023年12月01日 再审阅日期Review before 2026年11月30日 分发部门Distribution QA,QC | [21A]固体检验标准操作规程 [21A]固体SOP | | | | | | | :---: | :---: | :---: | :---: | :---: | :---: | | 制定人Prepared by | 包 | 2023年1月27日 | 制定部门D | partment | 质量部 | | 审核部门Review Unit | QA | | QC | | | | 审核人Reviewed by | 每们 | | 这级丰 | | | | 审核日期Reviewed Date | 2023. 11.27 | | | | | | 批准人Approved by | 陈,䞍 | 批准日期Approved Date | | $2023^{\prime} 1127$ | | | 生效日期Effective Date | 2023年12月01日 | 再审阅日期Review before | | 2026年11月30日 | | | 分发部门Distribution | QA,QC | | | | |

  1. APPEARANCE DESCRIPTION


1.1. Visual inspection under natural light should be yellowish-white to white crystal powder.

  2. IDENTIFICATION
  2.1. The peak time of the main peak should be consistent with that of the standard

  3. WATER


3.1. Take 1.0 g of the test sample, accurate to 0.0001 g, and use Karl Fischer reagent according to CMC-SOP-QC-014-02 "Karl Fischer Water Determination Standard Operating Procedures".

3.2. Calculation formula: moisture ( % % %\% ). = V × F / m / 10 = V × F / m / 10 =VxxF//m//10=\mathrm{V} \times \mathrm{F} / \mathrm{m} / 10

  where m: weight of the test sample (g)
  V: Karl Fischer reagent consumption volume (mL)
  F: Water equivalent ( mg / mL ) ( mg / mL ) (mg//mL)(\mathrm{mg} / \mathrm{mL})

4. ASSAY AND RELATED COMPOUNDS

  4.1. Solution preparation method
  4.1.1. Diluent: mobile phase A A AA

4.1.2. Tryptonol stock solution: weigh 25 mg of tryptonol in 25 ml, dissolve it with dilution and set volume.


4.1.3. System suitability solution: Weigh 20 mg of [21] working standard into a 50 ml volumetric flask, then add 0.1 ml of trypin stock solution, dissolve with dilution and set volume.

4.1.4. Sample solution: Weigh 20 mg of sample into a 50 ml volumetric flask, dissolve it with diluent and set volume.


4.1.5. Control solution: Weigh 20 mg of [21] working standard into a 50 ml volumetric flask, dissolve with diluent and set volume.

  4.2. Chromatographic conditions and operating procedures
  4.2.1. Chromatographic conditions:

- Flow phase A: 6 ml phosphoric acid was added to 670 ml of water, mixed well, filtered with a 0.45 um filter membrane, and then 330 ml of methanol was added.

  - Mobile phase B: methanol.

- Column: Agilent SB-C8 column 4.6 mm × 250 mm × 5 um 4.6 mm × 250 mm × 5 um 4.6mmxx250mmxx5um4.6 \mathrm{~mm} \times 250 \mathrm{~mm} \times 5 \mathrm{um}


-Flow rate: 1.0 ml / min 1.0 ml / min 1.0ml//min1.0 \mathrm{ml} / \mathrm{min} ; Wavelength: 214 nm ; Column temperature: 30 C 30 C 30^(@)C30^{\circ} \mathrm{C}


  - Injection volume: 5ul
  Running time: 25min
  Time (minutes)   Mobile phase A ( % ) A ( % ) A(%)\mathrm{A}(\%)   Mobile phase B ( % ) B ( % ) B(%)\mathrm{B}(\%)   elution
0 5 0 5 0-50-5 100 0   Isocracy
5 25 5 25 5-255-25 100 30 100 30 100-30100-30 0 70 0 70 0-700-70   Linear gradients
时间(分钟) 流动相 A(%) 流动相 B(%) 洗脱 0-5 100 0 等度 5-25 100-30 0-70 线性梯度| 时间(分钟) | 流动相 $\mathrm{A}(\%)$ | 流动相 $\mathrm{B}(\%)$ | 洗脱 | | :---: | :---: | :---: | :---: | | $0-5$ | 100 | 0 | 等度 | | $5-25$ | $100-30$ | $0-70$ | 线性梯度 |
  4.2.2. Operation procedure:

- Inject 1 needle of blank solution, 1 needle of system suitability solution, 3 needles of control solution, 2 needles of sample solution, and 1 needle of control solution, and operate according to CMC-SOP-QC-014-04 "Standard Operating Procedures for High Performance Liquid Chromatography", and record chromatograms.


- Requires the resolution of the tryptol in the solution for system suitability to [21 5.0 5.0 >= 5.0\geqslant 5.0 ].

  4.3. Calculation method:

4.3.1.[21] The formula for calculating the content is as follows: A u = R u W S A s / R s W u A u = R u W S A s / R s W u Au=Ru**W_(S)**A_(s)//R_(s)WuA u=R u * W_{S} * A_{s} / R_{s} W u where: As: content of working standard \%;


Peak area of [21] of the Ru sample solution; Wu: sample weight mg;

  Rs: peak area of [21] in control solution;
  Ws: working standard weight mg;

  4.3.2. Impurity calculation methods


- Phenylhydrazine hydrochloride: percentage × 3.94 , 3.94 × 3.94 , 3.94 xx3.94,3.94\times 3.94,3.94 of area is the correction factor for phenylhydrazine hydrochloride


-o-methylphenylhydrazine hydrochloride: percentage × 3.74 , 3.74 × 3.74 , 3.74 xx3.74,3.74\times 3.74,3.74 of area is the correction factor for o-methylphenylhydrazine hydrochloride


-o-ethylaniline: percentage × 4.34 , 4.34 × 4.34 , 4.34 xx4.34,4.34\times 4.34,4.34 of area is the correction factor for o-ethylaniline


-o-ethylphenylhydrazine hydrochloride: percentage × 4.53 , 4.53 × 4.53 , 4.53 xx4.53,4.53\times 4.53,4.53 of area is the correction factor for o-ethylphenylhydrazine hydrochloride


- Tryptonol: Percentage × 0.83 , 0.83 × 0.83 , 0.83 xx0.83,0.83\times 0.83,0.83 of area is the correction factor for tryptonol


-7-Methyltryptonol:Area × 0.81 , 0.81 × 0.81 , 0.81 xx0.81,0.81\times 0.81,0.81 percentage is the correction factor for 7-methyltryptonol


- Any other single impurities are calculated using the area normalization method and related calculation methods:


- The total impurities are the sum of the impurities, if the impurities have a correction factor, the correction factor needs to be added for calculation


- In the chromatogram, phenylhydrazine hydrochloride, o-methylphenylhydrazine hydrochloride, o-ethylphenylhydrazine hydrochloride, o-ethylaniline, tryptohydrol 7-methyltryptonol has retention times of RRT 0.16, 0.21, 0.26, 0.35, 0.68, 0.86 relative to the main peak
  5. REVISION HISTORY

File encoding Issue No.
文件编码 Issue No.| 文件编码 | | :---: | | Issue No. |

Effective Date Effective Date
生效日期 Effective Date| 生效日期 | | :---: | | Effective Date |

Reason and content of the change Revised Details
变更原因及内容 Revised Details| 变更原因及内容 | | :--- | | Revised Details |
CMC-SOP-QC-003-47-00   2012-04-15   New
CMC-SOP-QC-003-47-01   2015-04-15   Revision of the document when it is due
CMC-SOP-QC-003-47-02   08/01/2017   The content and related substance methods have been revised
CMC-SOP-QC-003-47-03   December 01, 2017   Increases 7-methyltryptonol impurity
CMC-SOP-QC-003-47-04   December 01, 2020   Upgrade at expiration
CMC-SOP-QC-003-47-05   December 01, 2023   Upgrade at expiration
"文件编码 Issue No." "生效日期 Effective Date" "变更原因及内容 Revised Details" CMC-SOP-QC-003-47-00 2012年04月15日 新增 CMC-SOP-QC-003-47-01 2015年04月15日 文件到期修订 CMC-SOP-QC-003-47-02 2017 年08月01日 修订了含量及有关物质方法 CMC-SOP-QC-003-47-03 2017年12月01日 增加7-甲基色醇杂质 CMC-SOP-QC-003-47-04 2020 年12月01日 到期升版 CMC-SOP-QC-003-47-05 2023 年12月01日 到期升版| 文件编码 <br> Issue No. | 生效日期 <br> Effective Date | 变更原因及内容 <br> Revised Details | | :---: | :--- | :--- | | CMC-SOP-QC-003-47-00 | 2012年04月15日 | 新增 | | CMC-SOP-QC-003-47-01 | 2015年04月15日 | 文件到期修订 | | CMC-SOP-QC-003-47-02 | 2017 年08月01日 | 修订了含量及有关物质方法 | | CMC-SOP-QC-003-47-03 | 2017年12月01日 | 增加7-甲基色醇杂质 | | CMC-SOP-QC-003-47-04 | 2020 年12月01日 | 到期升版 | | CMC-SOP-QC-003-47-05 | 2023 年12月01日 | 到期升版 |