Risk Management Strategies for Biofilms in Water Systems used in Sterile Drug Manufacturing

• Regulatory frameworks such as EU GMP Annex 1 mandate stringent control of biofilms in pharmaceutical water systems. Water systems supplying sterile manufacturing must be validated, continuously monitored, and routinely sanitized to prevent microbial proliferation.
• Biofilm management begins with robust system design eliminating dead legs, ensuring continuous recirculation, and enabling effective drainage.
• Preventive measures include scheduled thermal or chemical sanitization, filtration barriers, and validated cleaning procedures. Integration of engineering controls with real-time analytics represents the gold standard for contamination prevention in aseptic processes.

What Are Biofilms and Why Are They a Risk in Sterile Drug Manufacturing?

Biofilms are communities of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix that adhere to surfaces. These hydrated microbial matrices attach to wetted surfaces in water systems and allow cells to grow protected from their surroundings. Biofilms can form in diverse natural and industrial environments, including on the interior surfaces of water system piping and tanks.¹

Microorganisms in a biofilm exist in a sheltered mode of growth that makes them highly resistant to cleaning and disinfection. The matrix acts as a protective barrier, enabling bacteria to survive exposure to antimicrobial agents that would kill free-floating cells. Embedded biofilm bacteria are notably more resistant to disinfectants and antibiotics, which allows them to persist on equipment surfaces. A mature biofilm can continually seed microorganisms into the surrounding water, acting as a chronic source of contamination even after routine sanitization.

Biofilms pose a serious contamination risk in sterile drug manufacturing because they harbor potentially pathogenic and pyrogen-producing microbes. Water systems in pharmaceutical facilities are a known reservoir for opportunistic Gram-negative bacteria (e.g. Burkholderia cepacia complex) capable to form resilient biofilms. Such bacteria are often isolated from pharmaceutical-grade water and can introduce endotoxins or viable cells into production processes. Even low-level microbial contamination in water for injection (WFI) can compromise sterile products, risking patient safety through endotoxin reactions or bloodstream infections. Contamination of parenteral drugs by biofilm-derived bacteria has caused serious public health incidents, including product recalls and outbreaks in vulnerable patients.

Once established, biofilms are difficult to eradicate and can lead to sporadic contamination of the water and products. Microbes residing in biofilms may not be detected by routine water sampling since they remain attached to system surfaces. These hidden biofilm communities can periodically release cells or endotoxins into the water stream, causing sudden spikes in microbial counts or pyrogen levels. Thus, a water system might appear in control until a biofilm fragments detach and infiltrate a batch of product. The unpredictable shedding of biofilm fragments creates an ongoing risk of contamination that requires constant vigilance in sterile manufacturing.²

The persistent and covert nature of biofilms makes them a major threat to aseptic operations. A comprehensive understanding of biofilm behavior is therefore essential in the pharmaceutical industry. Manufacturers must recognize that biofilms can form even in well-maintained systems and that these structures drastically increase contamination risk. Ultimately, controlling biofilm risks is critical to ensuring that sterile biologic products remain free of microbial contaminants and pyrogens. For this reason, the industry has devoted substantial effort to developing strategies to prevent biofilm formation and to mitigate any biofilm that does arise. In the following sections, we discuss how biofilms develop in water systems and outline gold-standard approaches to manage and monitor these risks in sterile drug production environments.

How Do Biofilms Form in Water Systems Used for Sterile Drug Production?

Biofilm formation is a multistep process beginning when free-floating microbes in the water attach to inner surfaces of the piping or tanks. Initially, planktonic microorganisms encounter the pipe wall and adhere through weak, reversible interactions. Given suitable conditions, these early colonizers firmly attach and start to secrete sticky polymers that anchor them to the surface, marking the transition from reversible to irreversible attachment.

Microorganisms produce extracellular polymers and form microcolonies on the surface. The matrix is composed of hydrated polymers that encapsulate the cells and glue the community together. As matrix production increases, the cells become embedded in a gelatinous layer that traps nutrients and protects the growing community. Within this matrix, the microbes proliferate and communicate, building a structured biofilm with water channels and gradients of nutrients and oxygen. Over time, the microcolonies expand and coalesce into a mature biofilm layer firmly affixed to  equipment surface.

The biofilm continues to mature as cells multiply and recruit other microorganisms from the water. In a pharmaceutical water system, the biofilm may include bacteria, fungi, or even protozoa that enter the system, creating a complex multi-species community. The metabolic activity of the biofilm microbes can change compared to free cells, often with slower growth rates and altered gene expression that further enhance their tolerance to biocides. The mature biofilm develops a three-dimensional architecture, with outer layers of active cells and inner layers of dormant or nutrient-deprived cells encased in EPS. This structure can reach a steady state where cell division is balanced by cell death and detachment.³

Eventually, portions of the biofilm may break off or release cells into the bulk water – a process known as dispersion. In the final stage of the biofilm life cycle, environmental or internal cues trigger some bacteria to exit the biofilm and return to a planktonic state. Clumps of biofilm or individual cells can slough away and be carried by the flowing water deeper into the system. This dispersal mechanism means that biofilms can seed downstream equipment or points of use with contaminants, spreading the biofilm problem within the water system. The detached cells can also colonize new surfaces, repeating the cycle and propagating biofilm formation to previously clean areas.

Certain environmental conditions in water systems strongly influence these biofilm formation steps. Zones of low flow or stagnation encourage initial bacterial attachment by allowing microbes prolonged contact with surfaces. If water is not continuously circulating, it creates favorable conditions for biofilm establishment. Adequate hydrodynamic conditions – meaning turbulent flow and elimination of stagnant pockets – are known to reduce biofilm accumulation. Temperature also plays a role: ambient temperatures can support microbial growth, whereas sustained elevated temperatures inhibit many organisms. Available nutrients in the water serve as fuel for microbial growth and matrix production. The characteristics of the surface material can influence adhesion as well – for instance, rough surfaces may allow easier initial attachment than highly polished stainless steel.

Without preventive measures, biofilm formation is likely to occur in any water system over time. Even with flowing conditions, biofilms can still form, and they tend to accumulate in areas that are not frequently cleaned or flushed. Thus, it is broadly accepted that biofilms will emerge in water systems unless specific controls are applied to prevent their establishment. Understanding how quickly biofilms can develop under conducive conditions underscores why proactive risk management is needed. By recognizing the factors that drive each stage of biofilm formation – from initial attachment to eventual dispersion – pharmaceutical manufacturers can better design their water systems and operational practices to interrupt the biofilm life cycle.⁴

The Role of Water Quality in Preventing Biofilm Growth in Drug Manufacturing

Maintaining excellent water quality is a cornerstone of preventing biofilm growth in pharmaceutical water systems. High-purity water with minimal organic content deprives microbes of the nutrients needed for biofilm formation. Pharmaceutical-grade water undergoes   multiple purification steps to remove organics, ions, and particulates, resulting in a microbiologically nutrient-poor environment less hospitable to microbial survival.

Water quality specifications for sterile drug manufacturing, extremely stringent. The microbiological limits for Water for Injection are typically <10 CFU/100 mL and endotoxin <0.25 EU/mL, reflecting the need for near-sterile water.⁵ Achieving these specifications in routine operation demands robust control of the water purification process and continuous of water quality monitoring. Any deterioration can rapidly lead to biofilm development on system surfaces. Temperature is another critical control  Traditional Water for Injection systems utilize hot storage and distribution (typically ~80 °C), whichprovides continuous thermal sanitization. . Hot WFI loops are largely self-sanitizing, since the elevated temperature continuously pasteurizes the water and the internal system surfaces.⁶ As a result, biofilms rarely form in properly maintained hot systems. In recent years, membrane-based ambient temperature WFI systems (“cold WFI”) have been introduced for energy efficiency, but they present a greater microbial risk if not carefully manager. Without benefit of heat, cold WFI systems depend on membrane integrity ,and chemical sanitization. Studies confirm that microbial proliferation is a significant challenge in ambient WFI loops, particularly  in storage tanks or complex distribution piping. To mitigate these risks, cold WFI systems require rigorous monitoring, ozone treatment, and more frequent sanitization cycles.⁷

Effective pretreatment of feed water is also essential. Source water can contain microbes and organic matter that seed biofilms if not adequately removed.  Modern water systems use multiple pretreatment steps to remove incoming bioburden and nutrients. By delivering high-quality feed water to the final purification steps, the burden on downstream units is reduced. Any failure in pretreatment, such as fouled membranes or UV lamp degradation, may introduce a microbial surge that promotes downstream biofilm growth. Thus, maintaining the integrity and performance of each purification step is an integral part of preserving overall water quality and preventing biofilms.⁸

Employing residual sanitants or periodic chemical treatments in the water can further suppress biofilm growth. While pharmaceutical water cannot be maintained with a constant disinfectant residual, intermittent use of sanitizing agents is common. For example, ozonated water can be used in storage tanks to provide continuous bactericidal action without leaving harmful residues. Periodic chemical sanitization with agents like peracetic acid or hydrogen peroxide can also be applied to clean biofilms from system components. Each sanitization method must be validated to ensure it effectively reduces microbial counts without contaminating the water with by-products. The choice of sanitization strategy depends on system design, but all aim to restore high-purity conditions that discourage biofilm persistence.

In summary, maintaining optimal water quality – characterized by low nutrients, controlled temperature, minimal bioburden, and appropriate chemical conditions – is fundamental to biofilm risk management. High water quality itself is a preventive measure: by removing the key ingredients that microbes need, the system becomes inhospitable for biofilms. All critical aspects of water quality are tightly monitored, and any deviation is swiftly corrected. Ultimately, water quality control and biofilm prevention are two sides of the same coin in pharmaceutical operations.

Key Risk Management Strategies for Controlling Biofilms in Water Systems

Effective biofilm risk management begins with sanitary design that minimizes stagnation, dead legs, and rough internal surfaces. System design is the first line of defense against biofilms. Water systems are engineered to eliminate stagnant regions, ensure continuous recirculation, and allow complete drainage. Pipework is typically sloped to allow complete drainage and made of high-quality materials (e.g. electropolished 316L stainless steel) that resist corrosion and microbial attachment. The design also ensures continuous circulation of water to avoid still zones where biofilms can easily initiate. An interdisciplinary approach that incorporates microbiology, engineering, and water chemistry considerations is used to build systems inherently less prone to biofilm issues.¹ For instance, installing smooth sanitary fittings, minimizing pipe lengths, and using appropriate gaskets and seals all contribute to a design that reduces biofilm niches. By addressing potential risk points at the design stage, companies significantly mitigate biofilm formation throughout the system’s lifecycle.

Routine sanitization remains a gold-standard biofilm control measure across pharmaceutical water systems. Sanitization can be achieved thermally or chemically, and it is performed on a scheduled basis to kill any microorganisms before they establish robust biofilms. Thermal sanitization (hot water or steam) is widely preferred for Water for Injection systems. Periodically raising the water temperature to sanitization levels (often ≥80 °C) for a defined period effectively inactivates bacteria and biofilms on internal surfaces. Hot water circulating at these temperatures can achieve several log reductions in microbial counts, as confirmed by studies modeling biofilm inactivation kinetics.⁶ Many WFI systems are designed to be maintained hot continuously, which serves as an ongoing preventive measure. For systems that cannot be kept hot, chemical disinfectants are used for sanitization. Common chemicals include ozone, chlorine dioxide, peracetic acid, or other approved biocidal agents, applied at intervals to eradicate biofilm microorganisms. Each sanitization cycle is followed by thorough flushing to remove chemical residues and biofilm debris. By adhering to a rigorous sanitization schedule (e.g. weekly or monthly, depending on system risk), manufacturers keep microbial levels low and disrupt incipient biofilms before they mature.

Physical filtration barriers play a crucial role in preventing and controlling biofilms. Point-of-use filters (typically 0.2 µm sterilizing-grade filters) are often installed on water outlets to ensure any bacteria or fragments from upstream biofilms are removed right before the water is used in production. Filtration barriers complement sanitization by intercepting microorganisms and biofilm fragments. Point-of-use sterilizing-grade filters protect critical applications near processing equipment and formulation steps. Upstream, reverse osmosis, ultrafiltration, and nanofiltration units remove cells and endotoxins. Integrity testing confirms performance after maintenance or excursions. Differential pressure monitoring detects fouling indicative of biofilm growth. Proactive changeout avoids breakthrough events jeopardizing water quality in biologics manufacturing.

Operational controls reduce contamination risks in water systems through disciplined procedures. Controlled loop velocities, routine flushing of seldom-used outlets, and timely gasket replacements limit attachment opportunities. Hygienic sampling techniques prevent false positives and cross-contamination. Controlled chemical additions employ validated limits and purge steps. Maintenance windows align with monitoring signals. Training embeds biofilm risk management into daily routines supporting sterile drug production.

Quality risk management frameworks prioritize mitigation where the probability and severity are greatest. Structured tools evaluate design, utilities, and usage patterns to rank failure modes. High-risk areas include heat exchanger crevices, poorly drained branches, and ambient segments. Targeted mitigations follow, including redesign, increased sanitization, or sensor addition. Periodic reviews incorporate monitoring data and deviation learnings. The approach links control measures to tangible risk reduction.⁸

Technology enhancements strengthen biofilm control measures beyond legacy practices. Online UV disinfection reduces planktonic bioburden in recirculating loops. Real-time total organic carbon monitoring flags nutrient ingress. Smart valves eliminate dead space. Automated CIP sequences harmonize thermal and chemical steps. Data historians correlate flow, temperature, and microbial signals. Together, these innovations create resilient, multi-barrier defenses aligned with water system validation expectations.

Best Practices for Monitoring Biofilm Risks in Sterile Drug Manufacturing

Comprehensive monitoring programs integrate culture-based testing with rapid methods to detect biofilm activity early. Routine total aerobic counts at strategic points verify control. Endotoxin testing supplements for Gram-negative risks. ATP assays provide same-day indications of biomass changes. Molecular tools characterize communities during investigations. Layered methods improve sensitivity across operating states in water systems in drug manufacturing.

Sampling plans rotate through all points of use within defined cycles. Frequency reflects product risk, system complexity, and historical performance. Pre-flush and post-flush protocols differentiate planktonic organisms from surface-associated sources. Disinfecting sampling valves prevents artifacts. Aseptic technique is rigorously trained, observed, and retrained. The goal is consistent, representative data informing biofilm monitoring in water programs.

Trend analysis transforms individual results into actionable insights for contamination risks in water systems. Control charts visualize drift toward alert levels. Seasonal overlays reveal environmental influences. Correlation of counts to temperature, flow, and maintenance identifies mechanistic drivers. Statistical rules trigger investigations before specifications fail. Documented reviews ensure quality ownership and timely response in sterile drug production.

Investigations follow structured pathways linking data to root causes. Teams verify sampling integrity, then localize sources using targeted swabs, borescopes, or removable coupons. Hypotheses consider stagnation, component wear, and nutrient intrusion. Corrective actions might include intensified sanitization, valve replacement, or loop balancing. Effectiveness checks confirm recovery. Lessons learned update procedures and the contamination control strategy.

Online indicators provide early warning between scheduled tests. Continuous temperature monitoring confirms thermal barriers. Differential pressure trends signal membrane fouling and potential biofilm accumulation. TOC spikes indicate organic ingress feeding EPS production. Flow sensors identify low-velocity segments. Integrated dashboards notify responsible personnel for rapid mitigation. Digital vigilance enhances biofilm prevention strategies reliably.

Governance structures ensure monitoring remains robust and current. Cross-functional reviews align microbiology, engineering, and operations. Periodic program effectiveness assessments benchmark detection capability against emerging risks. Method validations are renewed after changes. Personnel competency is tracked through qualifications and proficiency checks. The culture emphasizes transparency, speed, and science-driven decision making for biofilm risk management.

Ensuring Compliance with Regulatory Standards for Biofilm Control in Water Systems

Regulatory authorities worldwide recognize the threat of biofilms in pharmaceutical water systems and have set clear requirements to mitigate this risk. Compliance with these regulatory standards is not optional – it is mandatory for any facility manufacturing sterile medicinal products. For example, the European Union’s GMP Annex 1 (revised 2022) explicitly calls for water treatment and distribution systems to be designed, constructed, and maintained in a manner that prevents microbial contamination and biofilm formation. Regulatory inspectors expect to see that firms have considered biofilm risks in their water system design and have taken appropriate preventive measures from the outset. If a water system’s design is found to facilitate biofilm formation (for instance, having unnecessary crevices or unused pipe branches), it would be cited as a compliance gap. Thus, alignment with regulatory standards begins with engineering controls that minimize biofilm risk by design.⁵

Authorities also require that water systems be qualified and validated to consistently produce water of acceptable microbiological quality. During qualification, extensive testing is done to show that the system can meet its microbial and chemical specifications under all operating conditions, including seasonal variations that might affect source water. The validation protocols typically include studies of hold times, worst-case stagnation, and the efficacy of sanitization procedures to ensure that biofilms do not proliferate. Regulators expect firms to demonstrate that their sanitization regimen (whether hot water, steam, or chemical) is capable of effectively removing or killing biofilms, supported by validation data. Ongoing validation (re-qualification) is required at regular intervals to confirm that the system remains in a state of control. If a system undergoes changes (like new filters or repaired piping), re-validation ensures that these changes have not introduced new biofilm risks. Essentially, compliance with standards means the company has documented evidence that their water system operates under consistent control, with robust capacity to prevent biofilm-related contamination over time.⁹

One of the prominent regulatory expectations is the implementation of scheduled sanitization and maintenance for water systems to prevent biofilms. Guidelines such as EU Annex 1 stipulate that sterilization or disinfection of the water system must be carried out according to a predetermined schedule (e.g. weekly, biweekly) and also performed immediately if monitoring indicates out-of-limit results. The goal is to ensure that any incipient biofilm is regularly taken down before it can fully establish. Compliance in this context means having written procedures that define the sanitization frequency, method, and acceptance criteria, and keeping detailed records of each sanitization cycle.⁵ Furthermore, after any chemical sanitization or regeneration, regulations require that the system be tested and not returned to production use until water quality is verified to be back within specifications. For instance, if a chemical disinfectant is used, the firm must flush the system and then test for both residual chemicals and microbial counts/endotoxin to confirm the system is clean. Only after passing these tests can the water be used in manufacturing. Regulatory auditors will review these records to ensure the firm consistently follows its sanitization schedule and that the results demonstrate effectiveness. Failing to sanitize on time or ignoring an out-of-spec microbial result without appropriate corrective action would be considered serious non-compliance. Therefore, adhering to a rigorous sanitization program is a key compliance metric tied directly to biofilm control.

Regulations also mandate regular monitoring and review of water system performance as part of the contamination control strategy. Annex 1 emphasizes that water systems must be monitored for chemical and microbial quality on an ongoing basis, and that trend data should be periodically assessed for any adverse patterns. Firms are expected to establish alert and action levels for microbial counts in their water (based on qualification data) and to investigate any excursions above those levels.

A holistic Contamination Control Strategy (CCS) that includes water systems is now a regulatory expectation, especially after the latest Annex 1 revision. The CCS is a comprehensive plan that assesses all contamination risks in sterile production and defines control measures for each. Water systems, given their central role, are a critical element of the CCS. Regulators expect companies to have identified biofilm formation in water as a contamination risk and to have integrated all the above controls (design, sanitization, monitoring) into their CCS documentation. This means that sampling plans, sanitization schedules, and maintenance of water systems should be clearly linked to the overall strategy to minimize contamination in the facility. The CCS approach encourages seeing the water system not in isolation but as part of the broader manufacturing ecosystem – for instance, linking water quality to equipment cleaning, or understanding how a failure in water could impact aseptic processing. Compliance auditors may ask to see the CCS document and verify that water system controls are appropriately detailed and implemented as described. They will look for evidence that management has considered worst-case biofilm scenarios (such as a long-unused line or a filtration failure) and put contingencies in place. The CCS should also drive continuous improvement; for example, if a new rapid test could enhance water monitoring, the strategy might include adopting it. Aligning with regulatory standards thus means not only having the technical measures in place, but also having a top-level strategic framework that ensures these measures collectively achieve robust biofilm control.¹⁰

Conclusion

The gold standard in biofilm control unites technical precision with regulatory rigor. Effective risk management of biofilms in pharmaceutical water systems demands a synergy of scientific understanding, engineering excellence, and procedural discipline. By integrating validated sanitization regimes, sanitary design, and continuous monitoring, manufacturers can suppress microbial colonization and sustain water quality. Beyond engineering and analytics, success relies on trained personnel who understand microbial behavior and system vulnerabilities.

Through validated design, scheduled sanitization, and proactive monitoring, manufacturers achieve compliance with global GMP expectations while minimizing contamination risk. Effective water system management aligns with Annex 1 principles of maintaining a contamination control strategy that encompasses every lifecycle stage. Sustained regulatory compliance demonstrates scientific mastery, operational excellence, and an unwavering commitment to patient safety in sterile drug manufacturing.

FAQ

Prepared by:

Joanna Królasik

Microbiological Laboratory Division Manager

j.krolasik@mabion.eu

Joanna Królasik

Microbiological Laboratory Division Manager

With 25+ years of experience in microbiology, Joanna specializes in managing high-performing laboratory teams and ensuring operational excellence across complex environments. Her work is guided by a deep understanding of microbiological processes and quality management systems, including ISO, HACCP, and GMP/GHP standards. Joanna takes pride in maintaining the highest level of scientific integrity and reliability in every project.

As a mentor, trainer, and internal auditor, Mabion’s expert combines technical expertise with a passion for knowledge-sharing. Joanna have trained and coached dozens of specialists, helping them develop key skills in method validation, food safety, and analytical procedures.

Joanna holds a PhD in biotechnology. She is the author of numerous scientific articles published in renowned Polish and international journals, as well as the co-author of patent PL233148, which describes a method for producing VRBG microbiological medium in tablet form for the identification of Enterobacteriaceae.

Jakub Knurek

Marketing Specialist

j.knurek@mabion.eu

Jakub Knurek

Marketing Specialist

Jakub Knurek is a marketing and business development expert specializing in CDMO operations with scientific and biopharmaceutical background. During the COVID-19 pandemic, he contributed to the development of the Novavax protein vaccine. As a side project, he runs his own pharma company.

As the author of numerous articles, he is recognized as an important voice of the younger generation of scientists. He is a member of Mabion’s representation at industry trade shows, including BIO International Convention 2025 in Boston, 2nd Global Biologics India 2025 in Hydrabad, CPHI 2024 in Milan, CPHI 2023 in Barcelona, Life Sciences Baltics 2023 in Vilnius. He actively participates in academic, business and industry discussions, such as the “Building the Future Pharma Workforce” panel at CPHI Milan 2024.

References

1. Erdei-Tombor P, Kiskó G, Taczman-Brückner A. Biofilm Formation in Water Distribution Systems. Processes. 2024; 12(2): 280.
2. Silva-Santana G, Sousa Sales FL, Ribeiro Aguiar A, Lima Brandão M. Pharmaceutical Contamination by Biofilms Formed of the Burkholderia cepacia Complex: Public Health Risks. Processes. 2025; 13(5): 1270.
3. Li Y, Qu Y, Yang H, Zhou X, Xiao P, Shao T. Combatting biofilms in potable water systems: A comprehensive overview to ensuring industrial water safety. Environ Microbiol Rep. 2023; 15(6): 445-454.
4. Sauer K, Stoodley P, Goeres DM, Hall-Stoodley L, Burmølle M, Stewart PS, Bjarnsholt T. The biofilm life cycle: expanding the conceptual model of biofilm formation. Nat Rev Microbiol. 2022; 20(10): 608-620.
5. European Commission. EU GMP Annex 1: Manufacture of Sterile Medicinal Products. 2022. ECA Academy.
6. Kaatz Wahlen L, Parker A, Walker D, Pasmore M, Sturman P. Predictive modeling for hot water inactivation of planktonic and biofilm-associated Sphingomonas parapaucimobilis to support hot water sanitization programs. Biofouling. 2016; 32(7): 751-61.
7. Santos TM, Lopes MET, de Alencar ER, Silva MVA, Machado SG. Ozonized water as a promising strategy to remove biofilm formed by Pseudomonas spp. on polyethylene and polystyrene surfaces. Biofouling. 2025; 41(2): 144-156.
8. Zhu L, Liang Y. Quality risk management for microbial control in membrane-based water for injection production using fuzzy-failure mode and effects analysis. PeerJ Comput Sci. 2024; 10: e2565.
9. Röder F, Sandle T. Microbial Contamination in Water Systems. PDA J Pharm Sci Technol. 2022; 76(5): 434-443.
10. van der Galiën R, Langen AL, Jacobs LJM, Sawant Raschdorf P, Xing A, van Amsterdam MC. Practical application of setting up an annual Contamination Control Strategy (CCS) assessment. PDA J Pharm Sci Technol. 2025: pdajpst.2024-003018.