Sterile Filtration Process Control: Meeting Regulatory Expectations

Sterile filtration is a pivotal process step in pharmaceutical manufacturing to ensure the sterility of injectable drug products. It eliminates microorganisms and particulates while safeguarding the integrity of a final product. Effectively managing and monitoring the sterile filtration process requires meticulous attention to manufacturing controls and encompasses key parameters such as flow rate, temperature, use time, and pressure. Pressure emerges as a critical factor, necessitating oversight to validate the efficacy of a filtration system and uphold the stringent standards of regulatory bodies such as the US Food and Drug Administration (FDA) and the European Commission.

Pressure monitoring of sterile filtration steps is a regulatory expectation for process design and is established during filter validation. According to the FDA’s 2004 guidance on aseptic processing, pressure, flow rate, and other factors that can affect filter performance and validation should be conducted using worst-case conditions, such as maximum filter use time and pressure (1). The agency set further guidelines for single filtration of biotechnology-derived products (BDPs) in its Biotechnology Inspection Guide Reference Materials and Training Aids (2).

EU guidelines for filtration parameters and routine process controls state that “results of critical process parameters (CPPs) should be included in the batch record” (3). The Parenteral Drug Association’s (PDA’s) technical report on Sterilization Filtration of Liquids specifies that “process time and pressure drop can affect bacterial retention test results,” and it advises that “pressure differential across the test filter during validation of the bacterial challenge test should meet or exceed the maximum pressure differential permitted during processing” (4).

Our organization has observed that companies initially exclude pressure monitoring of sterile filtration in their drug-product manufacturing processes, which leads to questions from regulators about their process controls. Although such companies had controls for staying within a validated flow, the FDA expressed concern about their lack of pressure-limit controls. Companies responded by implementing upstream pressure monitoring and setting pressure limits aligned with filter validation.

Those biomanufacturers implemented two process-control strategies, the first of which was continuous automatic pressure monitoring. Continuous monitoring using a pressure sensor is only possible for processes with high flow rates. The second strategy involved intermittent manual monitoring throughout filtration.

As part of implementation, one company categorized filtration pressure as a CPP and set the maximum value based on filter-validation studies. Management justified critical categorization based on the ability of parameters to affect sterility. The filter supplier conducted initial validation studies to monitor pressure and establish a validated flow rate, taking a conservative approach by setting the upper limit for process filtration at the lowest observed upstream pressure. Furthermore, a risk assessment was conducted to evaluate the compatibility of the pressure sensor with the product, considering construction material and the potential presence of leachables and extractables. No additional leachable studies were needed because of the low surface area and contact time.

Current trends in biologics manufacturing have highlighted the importance of pressure monitoring for sterile filtration of vaccines based on lipid nanoparticle (LNP)-encapsulated mRNA and glycoconjugates. Studies have shown the heightened risk of filter fouling with such products and the importance of monitoring pressure to minimize the impact to bacterial retention and product sterility (5).

As supported by current trends in biologics manufacturing, particularly in the context of advanced vaccines, the importance of pressure monitoring for sterile filtration cannot be overstated. Incorporating such controls into manufacturing practices will help ensure the integrity and sterility of pharmaceutical products.

References

1 Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practice. US Food and Drug Administration: Rockville, MD, 2004; https://www.fda.gov/media/71026/download.

2 Biotechnology Inspection Guide (11/91). US Food and Drug Administration: Rockville, MD, 2014; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/biotechnology-inspection-guide-1191.

3 Annex 1: Manufacture of Sterile Medicinal Products. The Rules Governing Medicinal Products in the European Union: Volume 4 — EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 2022; https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf.

4 TR 26. Sterilizing Filtration of Liquids. Parenteral Drug Association: Bethesda, MD, 2008.

5 Messerian KO, et al. Pressure-Dependent Fouling Behavior During Sterile Filtration of mRNA-Containing Lipid Nanoparticles. Biotechnol. Bioeng. 119(11) 2022: 3221–3229; https://doi.org/10.1002 bit.28200.

Libby Russell, PhD, is vice president and senior consultant at Syner-G BioPharma Group, 100 Pennsylvania Avenue Suite 310, Framingham, MA 01701; [email protected].