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Regulatory Expectations for Sterile Filtration Process Control

Sterile filtration is a critical process step in the production of injectable drug products and is used to remove microorganisms and particulates from a product stream to ensure purity and sterility of the product. Manufacturing controls are required to successfully monitor and manage a sterile filtration process to achieve the desired product quality. Process parameters considered for manufacturing control can include, but are not limited to, flow rate, temperature, use time and pressure. Monitoring the differential pressure across a filter is an important process parameter to control to ensure that the filter is performing as expected and achieving the target product sterility of the final stream.

Pressure monitoring of sterile filtration steps is an expectation for process design and is established during filter validation to ensure product sterility. Pressure monitoring during sterile filtration is not a new expectation in industry. In fact, this expectation is captured in multiple regulatory and industry guidance documents. For example:

FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing- CGMP Section IX-B Filtration Efficacy

Per FDA Guidance for Industry: Factors of pressure and flowrate can affect filter performance and filter validation should be conducted using worst-case conditions, such as “maximum filter use time and pressure”.

PDA TR26: Sterilizing Filtration of Liquids

“Process time and pressure drop can affect bacterial retention test results.” “The pressure differential across the test filter during validation of the bacterial challenge test should meet or exceed the maximum pressure differential permitted during processing (within the filter manufacturer’s design specifications).”

FDA Biotechnology Inspection guide reference materials and training aids: Processing and Filling

Whereas double filtrations are relatively common for aseptically filled parenterals, single filtration at low pressures are usually performed for BDP [biotechnology derived product]. It is for this reason that manufacturing directions be specific, with maximum filtration pressures given.”

EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products

8.85 Filtration parameters that should be considered and established during validation should include, but are not limited to: (ii) Filtration process conditions including: Maximum operating pressure, flow rate

8.86 Routine process controls should be implemented to ensure adherence to validated filtration parameters. Results of critical process parameters should be included in the batch record, including but not limited to the … and pressure difference across the filter.”

At Syner-G BioPharma Group, we have seen recent examples of companies not initially including pressure monitoring of sterile filtration in the drug product manufacturing process for biologics, resulting in questions from the FDA regarding their process control. While controls for staying within a validated flow rate were in place, the FDA expressed concern that a pressure limit control was not in place.  In these cases, the companies responded by implementing pressure monitoring upstream of the sterile filter and setting pressure limits aligned with filter validation.

Two process control strategies were implemented:

  • Continuous automatic pressure monitoring. This control was only possible for a process with a higher flow rate. Lower flow rates resulted in erratic pressure readings.
  • Intermittent manual monitoring at the beginning, middle and end of filtration.

As part of the implementation, the filtration pressure was categorized as a critical process parameter and the maximum value was set based on filter validation studies.  The categorization of critical was rationalized based on the ability of the parameter to impact sterility.   The initial filter validation studies were conducted by the vendor to establish a validated flow rate.  During these validation studies, the filter vendor also monitored pressure over the duration of the study.  A conservative approach was taken and the upper limit for process filtration was set as the lowest observed upstream pressure.

Additionally, the pressure sensor was assessed for product compatibility based on material of construction as well as potential leachables and extractables in a risk assessment. For this process, no additional leachables studies were needed based on the low surface area and contact time. Depending on the process lifecycle, these implementation measures might not be necessary as they are only necessary for approval of commercial manufacturing processes.

Current trends in biologics manufacturing have highlighted the importance of pressure monitoring for sterile filtration as it relates to the recent mRNA lipid nanoparticle vaccines, glycoconjugate vaccines and cytomegalovirus vaccines. Several studies have shown the heightened risk of filter fouling with these products and the importance in monitoring pressure to minimize the impact to bacterial retention and product sterility.

Messerian, K. O., Zverev, A., Kramarczyk, J. F., & Zydney, A. L. (2022). Pressure-dependent fouling behavior during sterile filtration of mRNA-containing lipid nanoparticles. Biotechnology and Bioengineering, 119, 3221–3229.

Du, Z, Motevalian, SP, Carrillo Conde, B, Reilly, K, Zydney, AL. Scale-up issues during sterile filtration of glycoconjugate vaccines. Biotechnol. Prog. 2022; 38(4):e3260.

Taylor, N, Ma, W, Kristopeit, A, Wang, S-C, Zydney, AL. Evaluation of a sterile filtration process for viral vaccines using a model nanoparticle suspension. Biotechnology and Bioengineering. 2021; 118: 106–115.

Taylor, N, Morris, M, Wee, A, Ma, W, Kristopeit, A, Wang, S-C, Zydney, AL. Bacterial Retention During Filtration of a Live Attenuated Virus Vaccine Through the Sartobran P Sterile Filter. Pharmaceutical Biotechnology. 2022; 111 (7): 1887-1895.

In conclusion, the regulatory landscape for sterile filtration in the production of injectable drug products is a complex terrain that demands meticulous attention to process control parameters, with a particular emphasis on pressure monitoring. Recent case studies have shed light on the critical role of aligning manufacturing practices with regulatory expectations, underscoring the significance of sterile filtration pressure control in ensuring product sterility. Recognizing the evolving nature of biologics manufacturing, especially with groundbreaking vaccines like mRNA lipid nanoparticle vaccines, glycoconjugate vaccines, and cytomegalovirus vaccines, staying informed about the latest research findings is crucial. Moreover, these challenges highlight the importance of connecting with experts at Syner-G. Leveraging the expertise of Syner-G’s professionals can provide invaluable insights and guidance in navigating the intricacies of regulatory compliance and optimizing sterile filtration processes. For a tailored approach to your specific challenges, connecting with a Syner-G expert is not just a recommendation; it’s a proactive step toward excellence in biopharmaceutical manufacturing.

Libby Russell, PhD.
Vice President & Senior Consultant

Libby brings over 20 years of experience in the bio/pharma industry with a focus on product and process development, commercialization and regulatory strategy.

Her work experiences in the biotech industry at Amgen, Inc. and Ophthotech had her leading product commercialization efforts overseeing analytical, tech transfer, validation, regulatory and process development activities.  She has experience working on a range of products and modalities for both drug substance and drug product GMP manufacturing including monoclonal antibodies, oligomers, glyco-proteins and vaccines. At Amgen, she was the Process Team Leader for a commercial monoclonal antibody product, supporting manufacturing at two commercial facilities. During her time at Ophthotech, as the Associate Director of Commercial Manufacturing, she oversaw the oligo-based API and Drug Product contract manufacturing implementing Operational Excellence to improve productivity. Her additional responsibilities included: process validation support, regulatory document authoring, technology transfer documentation and commercial support.

She received her Ph.D. in Chemical Engineering from the University of Colorado-Boulder studying protein aggregation in cell