The Era of PUPSIT Arrives! BioLink’s Solutions Address Compliance Challenges in Sterile Filtration

With the release of the draft appendix for sterile pharmaceuticals in the Good Manufacturing Practice (2010 Revision), the industry’s focus on compliance in sterile drug production has significantly increased.

Article 187 of the draft states:“Sterilizing filter assemblies should undergo integrity testing after sterilization and before use.” Currently, while the FDA does not mandate PUPSIT (Pre-Use Post-Sterilization Integrity Testing), other regulatory bodies such as the EMA, PIC/S, MFDS, and PMDA require it for sterilizing filters. It is evident that PUPSIT for sterilizing filters has become inevitable.

As a professional supplier of critical process equipment and consumables, BioLink offers PUPSIT systems and accessories tailored to customer needs, leveraging full-process localization capabilities to support compliance upgrades.  

Why PUPSIT is Essential

Sterile filtration, a physical method to remove microorganisms from liquids or gases in direct contact with pharmaceuticals, is critical in sterile drug production. For non-terminally sterilized products, sterility relies on the filtration system and aseptic processes. The integrity and sterility of the filter are prerequisites to ensure product sterility. PUPSIT verifies that the filter remains undamaged during assembly, sterilization, transportation, storage, unpacking, and installation, ensuring sterile filtrate. This enhances sterility assurance and patient safety while reducing the risk of batch loss due to pre-filtration system failures.

PUPSIT Design Considerations

PUPSIT introduces contamination risks to the downstream process, such as additional gas/water discharge lines and valves. Thus, its design and operational standards are crucial.

Figure 1. Typical PUPSIT System Design

1. Single-step or Redundant Sterile Filtration?

The single-step sterile filtration system, while relatively simple in PUPSIT design and operation with lower costs and less product loss, carries higher risks. If the integrity of the single sterilizing-grade filter fails, there is no remedial measure available. Additionally, according to the Guidelines on Sterilizing Filtration Technology and Applications, single-step sterile filtration is more likely to face scrutiny during audits.

Redundant sterile filtration provides dual protection, higher fault tolerance, and compliance advantages. However, it requires more complex operations, validation (including dual-filter integrity testing), and additional costs and space.

The choice between a single-step filter and a redundant filter system requires comprehensive evaluation based on specific application scenarios, regulatory requirements, cost considerations, and safety factors. Consequently, redundant sterile filtration may be the more appropriate option for high-risk or high-value products.

2. Water Wetting or Product Wetting

When selecting between water wetting and product wetting in sterilizing-grade filtration processes for pharmaceutical preparations, the following factors should be considered:

·Water wetting simplifies integrity testing

Water wetting simplifies integrity testing (e.g. bubble point, diffusion flow) with standardized parameters but may require drying for incompatible products. Product wetting reflects real-world performance but needs product-specific validation. The choice depends on filter type, product risk, process requirements, and historical data.

·Process Compatibility:

Water wetting fits for all filter types and serves as a universal testing method to ensure filter integrity before product filtration. However, product-water compatibility must be considered. If fails, post-test drying is required. Product wetting more accurately reflects the filter’s performance under actual operating conditions but product-specific validation and testing are necessary.

·Risk Assessment:

For low-risk products with infrequent filter use, water wetting may suffice. For high-risk products or frequently used filters, product wetting provides more accurate test results, thereby reducing the risk of product contamination.

·Production and Operational Convenience: 

Water wetting offers simpler operation and faster testing, making it suitable for routine inspections. Product wetting may require additional preparation and adjustments but provides more specific process suitability data.

In summary, the choice between water wetting and product wetting should be based on comprehensive evaluation of filter type, product risk characteristics, production process requirements, and historical validation data. Prior to finalizing the decision, it is recommended to thoroughly evaluate and validate both methods' impacts on filter performance and product safety.

3. Monitor upstream pressure only or both upstream and downstream pressures

The answer is definitive. According to the“Sterilizing Filtration Technology and Application Guidelines,”sterilizing filtration must be conducted within specified process parameters, including but not limited to filtration temperature, time, pressure, and differential pressure across the filter. Article 186 of the draft Annex for Sterile Products explicitly states: “The sterilizing filtration process shall be validated, and critical process parameters shall be recorded in batch records, including but not limited to the time required to filter a specific volume of product and the pressure on both sides of the filter.”However, most pharmaceutical companies currently still adopt practices of monitoring only upstream pressure or not monitoring filtration pressure at all. When only upstream pressure is monitored, it is generally assumed that the downstream side of the filter is open to atmospheric pressure, thus defaulting to zero or negligible pressure. With the implementation of new regulations, approaches that monitor only upstream pressure or neglect pressure monitoring altogether will face increasing scrutiny during audits.

BioLink High-Compliance Solutions

1. Single-Use PUPSIT Systems Manufactured in B+A Environments

To ensure the safety of filling processes and achieve cleaner fluid transfer during filling operations, BioLink has established B+A production environments for sterile formulation filling products. By integrating customers' specific processes and facility equipment, we provide comprehensive customized solutions covering intermediate preparation, filtration, liquid storage, and filling operations. This ensures superior cleanliness while significantly reducing particulate matter and visible particles.

For PUPSIT systems, BioLink delivers 100% customized solutions tailored to different process characteristics and critical considerations. Each assembled system undergoes 100% integrity testing to eliminate leakage risks, ensuring reliable performance for end-users.

Figure 2: PUPSIT case

2. BioHub® PAT

BioHub® PAT is an electronic data recording device for monitoring pressure, temperature, and flow in pipelines or containers during R&D or production processes. It records and automatically calculates single-point pressure values, ΔP (differential pressure), and TMP (transmembrane pressure). The device features access control, audit trails, data recording, monitoring alarms, and real-time printing capabilities, while maintaining compatibility with most mainstream disposable pressure and flow sensors available on the market.

BioHub® PAT can be utilized for pressure monitoring on both sides of filters within PUPSIT systems, ensuring full compliance with regulatory requirements.

Figure 3. BioHub® PAT

3. BioHub® Single-use Pressure Sensor

The BioHub® Single-use Pressure Sensor is suitable for various process stages including cell culture, chromatography, depth filtration, nanofiltration, ultrafiltration, and sterilizing filtration. It provides precise monitoring solutions for aseptic processes, helping to ensure smooth production operation through digital monitoring and simplified process control. The fluid-contact material is PSU, compliant with USP Class VI requirements, with an operational pressure range of -0.79 to 5.2 bar and an accuracy of ±2%.

The single-use pressure sensors can be employed for pressure monitoring on both sides of filters in PUPSIT systems.

 Figure 4. BioHub® Single-use Pressure Sensor

4. BioHub® PUPSIT Platform

Redundant filtration systems present inherent design and operational complexities, requiring advanced personnel training and substantial operational space. In response to pharmaceutical manufacturers' needs, BioLink offers customized PUPSIT platform solutions that significantly streamline operational procedures while minimizing losses caused by human error. Our platforms can be tailored to support either semi-automated or fully-automated configurations based on specific PUPSIT system requirements.

Figure 5.BioHub® PUPSIT Platform

Conclusion

The release of the draft Annex for Sterile Products to the Good Manufacturing Practice (2010 Revision) signifies China's full alignment with international regulatory standards, making PUPSIT for sterilizing filters an imperative. With self-developed technologies, a controllable supply chain, and agile services as core competitive advantages, BioLink is committed to delivering cost-effective, highly compliant localized solutions for sterile pharmaceutical manufacturing.