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I. Material Receiving and Temporary Storage

Material Receiving Process

Upon the arrival of materials, the following checks must be performed:

· Information Verification: Confirm material name, batch number, quantity, supplier qualification, and quality test reports (COA).

· Visual Inspection: Ensure the outer packaging is intact and undamaged, and label information is clearly legible.

· Storage Condition Verification: Check that the material is stored under the required environmental conditions, especially for temperature-sensitive raw materials.

Temporary Storage Management

· Store materials according to their storage requirements (e.g., refrigerated, cool, or ambient temperature) in the appropriate warehouse or area.

· Follow the "First In, First Out" (FIFO) principle for issuing materials.

· Implement controlled environment storage for critical materials to ensure their quality remains unaffected.

II. Material Transfer and Weighing Operations

Material Transfer Guidelines

· Conduct transfer in a clean area (typically Class C with Class A laminar flow protection).

· Use sterilized or cleaned dedicated containers and tools.

· Implement measures to prevent contamination and cross-contamination during transfer.

Weighing and Measuring Operations

· Perform operations in a weighing room equipped with an independent ventilation system.

· Ensure all weighing scales and measuring instruments are regularly calibrated for accuracy.

· Implement a dual-person verification system, where one person performs the operation and another supervises and confirms.

· Operators must wear protective clothing appropriate to the cleanroom classification and strictly follow operating procedures.

· Ensure all weighing data is fully documented and traceable.

III. Solution Preparation Process

Preparation Environment and Equipment Requirements

· Prepare solutions in a Class C clean environment with Class A laminar flow or isolator protection.

· All equipment coming into contact with materials (e.g., preparation tanks, mixers, pipelines) must be cleaned and sterilized (e.g., moist heat sterilization or SIP).

· Equipment must complete Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).

Process Control During Preparation

· Strictly follow approved formulas and operating procedures.

· Control dissolution sequence, mixing speed, time, and temperature as critical parameters.

· Continuously monitor pH, conductivity, concentration, and other indicators to ensure solution homogeneity and stability.

· Record all operational steps and in-process control results.

Solution Stability Management

· Assess the chemical, physical, and microbial stability of the prepared solution.

· Determine the maximum allowable hold time from preparation to filtration or filling, and validate it.

IV. Sterile Filtration of the Drug Solution

Purpose of Filtration

· Remove microorganisms and particulate impurities from the drug solution through sterile filtration to ensure product sterility.

Filter Selection and Validation

· Select appropriate filter material (e.g., polyethersulfone, polyvinylidene fluoride) and pore size (0.22 μm or 0.1 μm) based on the solution’s characteristics (e.g., viscosity, adsorption, compatibility).

· Filters should come with integrity test certificates and validation data provided by the supplier.

Filtration System Configuration

· The system typically includes a pre-filter and a main sterile filter. Filter components must be pre-assembled and sterilized (either through online SIP or off-line sterilization followed by aseptic connection), and an integrity test must be conducted before use.

Filtration Operation Standards

· Conduct operations in a Class A clean environment.

· Control filtration pressure and flow rate to prevent filter blockage or damage.

· Perform integrity testing (e.g., bubble point test, diffusion flow test) before and after each filtration. If the test fails, the solution must not be used.

Post-Filtration Solution Management

· Store filtered drug solution in a sterile, sealed container, and if necessary, connect it to a sterile vent filter.

· Strictly control storage time and environmental conditions (e.g., temperature, light protection), and validate these conditions.

V. Transfer of Drug Solution to Filling Buffer Tank

Transfer Methods

· Transfer the solution via pressure or pump through sterile piping connections. Critical connection operations must be performed in a Class A laminar flow hood or isolator to ensure sterility.

Buffer Tank Requirements

· The buffer tank must be pre-sterilized (SIP).

· It should be equipped with a mixing device (if required), temperature control system, and sterile vent filter.

· It must have a liquid level indicator for monitoring.

Transfer Process Monitoring

· Monitor the solution status, whether the transfer is smooth, and any leakage.

· Ensure the solution properties remain unchanged.

VI. Online Monitoring and Control of Drug Solution Before Filling

Temperature Control

· Continuously monitor and adjust the solution temperature for temperature-sensitive products.

Mixing Control

· For suspensions or emulsions, control mixing speed and time to maintain homogeneity.

Pressure Control

· Maintain positive pressure inside the tank using sterile gas (e.g., nitrogen) to prevent external contamination.

Time Control

· Strictly control the storage time of the solution in the buffer tank, which must not exceed the validated maximum allowable time.

Sampling (Optional)

· Perform sampling at the beginning or during the filling process for rapid testing (e.g., pH, appearance) or retention samples.

VII. Key Control Elements Throughout the Process

Cleanroom Environment Management

· The cleanroom must meet the corresponding air cleanliness standards (e.g., Class C or D background with Class A operation areas).

· Regularly monitor airborne particles, microbial levels, temperature, humidity, and pressure differentials.

Personnel Training and Behavior Standards

· Operators must receive training in aseptic techniques, GMP, and SOPs.

· Follow garbing, hand hygiene, and cleanroom behavior protocols.

Equipment Qualification and Maintenance

· All equipment that contacts the drug solution must complete IQ/OQ/PQ qualification.

· Regular calibration and maintenance are required to ensure stable equipment performance.

Process Validation

· The entire material handling and preparation process must be validated to ensure consistency and reliability.

Documentation and Record Management

· All operational records, test data, equipment usage, and cleaning and sterilization logs must be complete, accurate, and traceable.

Change and Deviation Management

· All changes must be evaluated and approved.

· Deviations must be recorded, investigated, and corrective actions taken promptly.

Prevention of Contamination and Cross-Contamination

· Control contamination risks through closed systems, one-way process design, cleaning procedures, and operator behavior controls.