Aseptic filling is a crucial process in modern pharmaceutical manufacturing, referring to the procedure of filling pharmaceutical products into containers under sterile conditions.

As the final step in the GMP production of biological drugs, aseptic filling services require professional expertise, sound design, and strict regulations to ensure the quality of the final drug product. A high-standard sterility assurance system runs throughout this highly complex continuous manufacturing process.

A complete manufacturing process for a biological drug product typically includes:

drug substance preparation and thawing, drug substance mixing, sterile filtration, aseptic filling, stoppering, (lyophilization), capping, visual inspection, release testing, labeling/packaging.

1. Drug substance preparation and thawing

Drug Substance preparation typically involves two scenarios:

(1) In the first scenario, all formulation components are added during drug substance manufacturing before final filtration, requiring no additional materials during drug product filling. In this case, the drug substance is typically stored frozen.

(2) In the second scenario, certain materials are added to the drug substance (particularly when the stability of certain components is a concern).

Drug substance thawing is typically conducted at room temperature, requiring strict control of thawing time and temperature. While longer thawing time results in more complete thawing, it also presents stability challenges for samples exposed to room temperature for extended periods.

2. Drug substance mixing

During "Drug substance preparation" or after thawing, mixing is required to ensure uniform distribution of drug substance components. Different products have varying sensitivities to shear forces, requiring careful control of stirring speed and duration during this phase.

3. Sterile filtration

After drug substance mixing, sterile filtration is performed to achieve aseptic conditions prior to filling. Typically, two sterilizing-grade filters are connected in series, with the sterilizing filter positioned closer to the filling point and a redundant filter upstream. Post-use filter integrity testing is performed on the sterilizing filter; if the sterilizing filter fails the integrity test, the redundant filter's integrity should be tested and must pass. Critical parameters during this phase include filter loading capacity and pressure. Inappropriate selection of sterilizing filter specifications may result in filter clogging during filtration, leading to reduced batch yield.

4. Aseptic filling & stoppering

Aseptic filling typically includes the following operations: pre-filling cleaning and sterilization of equipment and utilities, component assembly, selection of filling programs and parameter settings. For aseptic manufacturing processes, filling is a high-risk operation where the post-filtration drug product is directly exposed to open air conditions. Therefore, it must be performed in a Grade A environment, and the time between filling and container closure should be minimized. The filling process should be validated, and environmental monitoring during filling should include airborne particle counts, surface microbial monitoring, viable airborne particles, and settling plates. For liquid formulations, stoppering and capping operations are performed immediately after filling.

5. Lyophilization & capping

For lyophilized products, after filling, vials undergo partial stoppering before entering the lyophilizer, followed by full stoppering and capping after lyophilization is complete. The capping process primarily prevents stopper dislodgement and ensures container closure integrity for long-term storage. During capping, metal particles and stopper fragments may be generated; therefore, inspection and contamination removal systems should be implemented. Automated inspection technology should be used before and after capping to reject defective products such as missing stoppers or caps. After capping, container closure integrity testing should be performed using validated methods.

6. Visual inspection

The purpose is to eliminate non-conforming filled products, such as broken vials, foreign particles, and fill volume defects.

7. Release testing

Products that pass visual inspection (manual inspection) undergo release testing, which typically includes product-related impurities, process-related impurities, potency, safety, and routine testing.

8. Labeling/packaging

For products that have passed visual inspection (manual inspection), labeling and packaging operations are performed. Prior to packaging, containers, packaging materials, labels, and label content should be verified to minimize the risk of packaging errors and mix-ups.

LKtime Biotech's drug product platform, serving the entire product lifecycle, can meet formulation prescription and development needs for various types of biological products including monoclonal antibodies, bi/multi-specific antibodies, vaccines, recombinant proteins, peptides and plasmids.

(1) Formulation Development

Support the formulation development for various types of biological products, such as antibodies, ADCs, recombinant protein vaccines, etc. By analyzing the data from developability assessment, the issue of product instability can be addressed during formulation development.

• mAb/BsAb/ADC: Stable liquid / lyophilized formulation
• Recombinant protein vaccines: Vaccine formulation development with aluminum-salt adjuvant, MF59, AS03, CpG etc.

(2) Drug Product Process Development

• Development of freeze-drying process
• Development of mixing process
• Development of aseptic filtration process

(3) Clinical Manufacturing

Provide non-GMP&GMP drug product production service.

• PFS Line
Vacuum plugging; Nitrogen protection (optional); Filling accuracy: ±3%
PFS: 1400 syringes/h; Cartridge: 1400 syringes/h

• Vial Line
Vial washing, drying, filling, and capping combined production line
2m² Freeze Dryer
Filling accuracy ± 3%
Lyophilized powder
2R: 8000 vials/batch; 10R: 3800 vials/batch; 20R: 1800 vials/batch
Liquid
2R: 3000 vials/h; 10R: 2400 vials/h; 20R: 2400 vials/h

(4) Technology Transfer and Optimization

Provide regulatory, document support, and process optimization service during product technology transfer.

• Differences and risk assessment
• Tech Transfer protocol and report
• Process control strategy
• Formulation optimization
• Lyophilization, mixing, filtration process optimization and scale-up

(5) Process Characterization

Following the QbD concept, we analyze the various process parameters of the DP process through risk assessment, experimental design, and data analysis to provide a robust design space for the process output.
• Freeze-thaw Process Characterization
• Mixing Process Characterization
• Formulation Robustness Study
• Filtration Process Characterization

• Freeze-Drying Process Characterization

(6) Post-Approval Change

Provide technical support and registration support for post-approval changes.
• Process change
• Packaging form change
• Strength change