1. Purpose
This Standard Operating Procedure (SOP) defines the detailed manufacturing process of Active Pharmaceutical Ingredient (API) by chemical synthesis, specifying the operation steps, process parameters, quality control points and safety requirements. The purpose is to ensure that the API is produced consistently in accordance with Good Manufacturing Practices (GMP), meets the pre-determined quality standards, and ensures the safety, efficacy and stability of the final product.
2. Scope
This SOP applies to all personnel involved in the API manufacturing process, including operators, process technicians, quality control (QC) inspectors, and supervisors. It covers the entire manufacturing process from raw material preparation to finished API packaging and storage, including both non-sterile and sterile API manufacturing (sterile process is supplemented in Annex 1).
3. Responsibilities
| Manufacturing Operator: | Strictly follow the operation steps specified in this SOP, record process parameters and operation details accurately and timely, and ensure the normal operation of equipment. |
| Process Technician: | Guide operators to carry out standardized operations, monitor process parameters, handle abnormal situations during the manufacturing process, and verify the rationality of the process. |
| QC Inspector: | Conduct sampling inspection at each key quality control point, test according to the corresponding quality standard, and issue inspection reports; supervise the implementation of quality control requirements in the manufacturing process. |
| Manufacturing Supervisor: | Responsible for the implementation and supervision of this SOP, organize personnel training, ensure that all operators are familiar with and master the content of this SOP, and review the operation records.
|
4. Definitions and Abbreviations
API: Active Pharmaceutical Ingredient
GMP: Good Manufacturing Practices
QC: Quality Control
SOP: Standard Operating Procedure
Quenching: The process of terminating a chemical reaction by adding a quenching agent to avoid side reactions.
Phase Separation: The process of separating the reaction mixture into two immiscible phases (organic phase and aqueous phase) after the reaction.
Recrystallization: A purification method to obtain high-purity products by dissolving crude products in an appropriate solvent and then crystallizing them.
5. Manufacturing Process Flow (English Version)
5.1 General Chemical Synthesis Process of Non-sterile API
Step 1: Raw Material Preparation (Charging/Feed Preparation)
Check the name, batch number, purity and expiration date of starting materials, catalysts and solvents, and confirm they meet the pre-determined quality standards (QC inspection report is required).
Weigh the starting materials, catalysts and solvents accurately according to the formula requirements, and record the weighing data (accuracy requirement: ±0.1%).
Transfer the weighed materials to the designated reaction vessel in sequence, and ensure no leakage or contamination during the transfer process.
Step 2: Chemical Synthesis (Reaction Step)
Close the reaction vessel, check the tightness of the vessel, and confirm that the stirring, temperature control and pressure control systems are normal.
Set the reaction parameters according to the process requirements: temperature (±2℃), pressure (±0.01MPa), stirring speed (±50rpm), and reaction time (±30min).
Start the stirring device, adjust the temperature and pressure to the set values, and start the reaction; record the reaction start time.
During the reaction process, regularly sample and detect the reaction progress (by HPLC or other specified methods) to ensure the reaction is complete (reaction completion standard: residual starting material ≤0.5%).
Step 3: Quenching & Phase Separation
After the reaction is confirmed complete, cool the reaction mixture to 20-30℃ under stirring.
Slowly add the pre-weighed quenching agent to the reaction vessel (adding speed: 5-10ml/min) to terminate the reaction, and continue stirring for 30-60min to ensure complete quenching.
Transfer the quenched mixture to a phase separation vessel, let it stand for 60-90min, and separate the organic phase and aqueous phase according to the phase boundary.
Discard the aqueous phase (or treat it according to the waste treatment SOP) and retain the organic phase (containing the crude product).
Step 4: Crude Product Isolation
Transfer the organic phase to a filtration/centrifugation device, and filter/centrifuge at 25-30℃, 1000-1500rpm to separate the solid crude product from the mother liquor.
Wash the crude product with an appropriate solvent (3-5 times the mass of the crude product) to remove residual impurities and solvents, and filter/centrifuge again.
Collect the crude product, weigh it, and record the yield (crude yield requirement: ≥85%).
Step 5: Purification
Option 1: Distillation/Extraction/Carbon Treatment
Transfer the crude product to a distillation device, set the distillation temperature (±5℃) and pressure (±0.005MPa), and distill to remove low-boiling impurities and solvents.
If extraction is needed, add the appropriate extractant to the distilled product, stir for 30-60min, stand for phase separation, and retain the target phase.
Add activated carbon (0.5-1.0% of the product mass) to the target phase, stir at 50-60℃ for 30min, and filter to remove activated carbon.
Option 2: Recrystallization (Preferred for High Purity Requirement)
Dissolve the crude product in a preheated solvent (solvent volume: 5-8 times the mass of the crude product) at 60-80℃, stir until completely dissolved.
Cool the solution slowly to 0-5℃ at a cooling rate of 2-5℃/h, and keep it warm for 2-4h to allow full crystallization.
Filter/centrifuge the crystallized mixture to separate the solid product, and wash it with a small amount of cold solvent (0-5℃) to remove residual impurities.
After purification, sample and send to QC for purity detection (purity requirement: ≥99.5%).
Step 6: Drying
Transfer the purified product to a drying device (vacuum oven or fluid bed dryer).
Set the drying parameters: vacuum oven (temperature: 60-80℃, pressure: ≤0.08MPa, drying time: 4-6h); fluid bed dryer (temperature: 50-70℃, air velocity: 0.5-1.0m/s, drying time: 2-4h).
During drying, regularly check the moisture content of the product (moisture requirement: ≤0.5%).
After drying is completed, cool the product to room temperature (20-25℃) under vacuum or inert gas protection.
Step 7: Milling & Sizing
Transfer the dried product to a milling device, adjust the milling speed (1000-2000rpm), and mill to the required particle size.
Sieve the milled product with a standard sieve (mesh size: 80-120 mesh), collect the product that passes the sieve, and re-mill the unqualified particles until they meet the requirements.
Sample and send to QC for particle size detection (particle size requirement: 90% of particles ≤100μm).
Step 8: Final QC Testing
Collect the finished product after milling and sizing, and send it to QC for comprehensive testing, including appearance, purity, moisture, particle size, heavy metals, residual solvents, etc.
Only when all test items meet the pre-determined quality standards can the product be regarded as qualified finished API.
Step 9: API Bulk Packaging & Storage
Pack the qualified finished API in clean, dry and sterile packaging containers (such as double-layer polyethylene bags, stainless steel barrels) under clean conditions (class D clean area).
Label each packaging container clearly, including product name (API), batch number, production date, expiration date, net weight, manufacturer, etc.
Store the packaged API in a dedicated storage room, with temperature controlled at 15-25℃, relative humidity at 45-65%, away from light, moisture and heat sources; store separately from other materials to avoid cross-contamination.
