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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 \%
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） >= 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 包   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 |