Executive Summary
Parenteral drug products, administered directly into the bloodstream, demand the highest manufacturing standards to ensure sterility and prevent contamination. The fill/finish process, as the concluding phase of aseptic parenteral drug production, requires the expertise of highly trained operators, the use of specifically designed equipment, and operation within advanced cleanroom environments to maintain this sterility.
In response to the industry's shift toward continuous processing and the growing demand for biologic drugs, the durability of silicone tubing in fill/finish operations becomes critical. To address this, a detailed technical engineering study was conducted to assess the performance of various tubing brands under operational conditions.
The study found that SaniSure®'s Pharm-A-Clear LH® tubing significantly outperformed its competitors, achieving up to 4.8 and 1.4 times more fills than both leading manufacturers in this space, respectively. This superior performance allows drug manufacturers to extend their fill runs, enhancing productivity while simultaneously reducing costs and risks, and confidently ensuring the safety of their products.
Introduction
Parenteral drug products, which are administered directly into the bloodstream, require rigorous manufacturing processes to ensure they remain sterile and free from contamination. While terminal sterilization is the method preferred by regulatory bodies due to its thoroughness, it is often unsuitable for many biologic drug substances. These substances are sensitive to the harsh conditions of sterilization, necessitating the use of aseptic processing techniques. Success in aseptic processing is dependent on the proficiency of trained operators, the efficacy of high-performing equipment, and the design of facilities and procedures tailored to maintain sterility.
Both stainless-steel and single-use equipment, along with consumables like tubing, must be sterile and capable of high performance under the conditions of aseptic manufacturing operations. The operational lifespan of consumables is particularly critical: the longer they can be utilized without compromising product specifications, the greater the number of container fills that can be executed before operations must be paused for equipment changeovers.
This paper delves into the specifics of fill/finish operations and the use of single-use equipment and consumables. It also examines regulatory expectations and presents the findings of a tubing engineering study that assessed the operational longevity of various tubing options designed for fill/finish applications. The study’s results underscore the importance of selecting the right materials to meet the stringent demands of aseptic processing, ensuring both efficiency and compliance with health regulations.
Essentials of Fill/Finish Operations
Fill/finish operations represent the final and crucial phase in the manufacturing of aseptic parenteral drugs. During this stage, sterile drug product solutions — predominantly biologics — are precisely dispensed into various containers, such as vials, bottles, cartridges, ampoules, and syringes. Minimizing human interventions is critical during these operations to mitigate the risk of contamination or damage to the primary packaging.
To ensure the maintenance of sterility, the process requires not only highly trained and skilled operators but also specially designed equipment and advanced cleanroom environments. Given the substantial investment required to develop these capabilities, many drug developers opt to outsource fill/finish operations to specialized contract service providers. This sector is experiencing significant growth, with the global aseptic fill/finish manufacturing market projected to expand at a compound annual growth rate of between 7.6% and 9%.1,2
The push towards greater efficiency and precision in fill/finish operations has led to the increased integration of automated systems. These systems utilize robotics and advanced data analytics to enhance the accuracy of the filling process and bolster quality control measures. Additionally, the shift toward continuous bioprocessing, which requires significantly extended operational periods, places additional demands on the durability and reliability of consumables, such as tubing and containers, used in these processes.
Single-Use Technologies in Fill/Finish
In fill/finish operations, the maintenance of sterility is paramount, necessitating the use of the highest-quality equipment and consumables that deliver superior performance over extended periods. While traditional manufacturing facilities for large-volume parenteral products often depend on stainless-steel fill/finish systems, modern production setups increasingly adopt single-use technologies (SUTs). These technologies, which are pre-sterilized and disposable, offer numerous advantages.
The absence of requirements for clean-in-place or steam-in-place operations with SUTs leads to quicker setup times. Additionally, single-use assemblies minimize the risk of contamination by significantly reducing human intervention during the manufacturing process. These technologies also allow for greater design flexibility and scalability in response to changing market demands, thereby enhancing operational efficiency, lowering costs, and elevating safety standards.
For optimal performance in fill/finish operations, SUT assemblies may comprise manifolds, tubing, pumps, and needles. Each component is carefully chosen based on the characteristics of the drug substance or final drug product, and the specific requirements of the filling operation, such as line speed, container type, volume, and duration of operation. It is crucial that these components support the filling process without introducing contaminants, causing degradation of the drug substance, or failing during the operation’s expected duration. This meticulous selection ensures that the final drug product is handled safely and efficiently, maintaining its integrity throughout the process.
Regulatory Compliance and Guidelines
Industry guidance on aseptic fill/finish operations has been issued by regulatory agencies in the US and Europe, as well as international bodies and industry trade groups such as the Parenteral Drug Association (PDA), and The International Society of Pharmaceutical Engineering (ISPE). Specific examples include the following:
Regulatory agencies in the United States and Europe, along with international organizations and industry trade groups, such as the Parenteral Drug Association (PDA) and The International Society of Pharmaceutical Engineering (ISPE), have established comprehensive guidelines for aseptic fill/finish operations. These include:
Industry Guideline on Sterile Drug Products Produced by Aseptic Processing, U.S. FDA, 1987.
ISO 13408-1 Aseptic Processing of Health Care Products, International Organization for Standardization, 2023
Annex 1, Manufacturer of Sterile Medicinal Products, Pharmaceutical Inspection Convention, 2003.
Validation of Aseptic Filling for Solution Drug Products, Parenteral Drug Association (PDA) Technical Monogram, Number 2, 1981.
Points to Consider for Aseptic Processing, PDA, 2003.
EudraLex: The Rules Governing Medicinal Products in the European Union. Volume 4: Good Manufacturing Practice (GMP) Guidelines. Annex 1: Manufacture of Sterile Medicinal Products. Brussels: European Commission, 2008.
These documents emphasize the critical need to conduct aseptic fill/finish operations within well-regulated environments, utilizing processes and equipment specifically designed to ensure sterility and protect product integrity. Furthermore, SUT assemblies used in fill/finish applications, including consumables like tubing, must demonstrate that they can maintain the sterility and integrity of the flow path while meeting operational requirements, such as duration, fill-volume accuracy, and more.
Guidelines also include testing protocols for single-use components:
U.S. Pharmacopeia 43, National Formulary 38 (USP), General Chapter <88> Class VI, Biological Reactivity Tests, In Vivo (2020)
U.S. Pharmacopeia 43, National Formulary 38 (USP), General Chapter <87> Class VI, Biological Reactivity Tests, In Vitro (2020)
ISO 10993-1: 2018 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
These regulations are crucial for ensuring that the equipment and procedures employed in fill/finish operations are safe, effective, and capable of consistently producing sterile pharmaceutical products.
Colanar FSP Peristaltic Pumps
Colanar FSP peristaltic pumps are tailor-made for pharmaceutical and biotechnological liquid filling applications, offering high precision in filling alongside an extended tube lifespan. These pumps are designed to apply minimal shear forces to biopharmaceutical products, preserving their integrity and quality. The key components that come into contact with products are disposable, ensuring a high standard of hygiene and safety.
The pump's exterior, including enclosures and heads, is constructed from durable 316L stainless steel, which can withstand rigorous cleaning and sterilization processes. A unique feature of these pumps is the ease with which the pump head can be detached from the base without any tools, simplifying the cleaning and maintenance tasks.
Moreover, the pumps are equipped with a PLC control system and servo drive that are securely housed within the pump enclosure to protect them from environmental exposure. An integrated touchscreen provides a user-friendly interface for operating the pump and programming filling recipes. The pumps are available in various configurations, making them suitable for everything from laboratory settings to full-scale Good Manufacturing Practice (GMP) production. The design of the PLC controls also facilitates straightforward retrofitting into existing fill lines, enhancing their adaptability and utility in diverse operational setups. This combination of features makes the Colanar FSP pumps a versatile and reliable choice for modern fill/finish operations.
Tubing Durability Study
A comprehensive tubing technical engineering study was undertaken to assess and compare the operational durability of various tubing brands used in filling operations. This study involved simulated filling operations where water was transferred from a reservoir using a Colanar FSP 1000 peristaltic pump. The specific tubing types examined were installed in the pump and connected to a 2.0-mm internal diameter filling needle to facilitate the dispensing process.
The tubing variants evaluated included SaniSure®’s Pharm-A-Clear Low Hysteresis® (LH), Competitor A, and Competitor B. Each of these is platinum-cured silicone tubing, a material choice specifically suited for peristaltic pump applications due to its durability and chemical compatibility. This study aimed to provide clear data on how each tubing type performs under controlled conditions, focusing on their endurance and reliability during extended use.
Results
The results of the filling runs with the three different types of tubing can be seen in Figure 1. The SaniSure® Pharm-A-Clear LH® tubing clearly outperformed the two competitors, achieving 4.8 times the number of fills as the Competitor B product and nearly 1.4 times that of the Competitor A tubing. It should be noted that the value for the Competitor B tubing was the average for two different runs. A second run was performed because the tubing broke in the first run.
The results from the tubing technical engineering study, depicted in Figure 1, highlight the superior performance of SaniSure® Pharm-A-Clear LH® tubing compared with its competitors. This tubing achieved 4.8 times the number of fills than the Competitor B product and nearly 1.4 times that of the Competitor A tubing. Notably, the data for the tubing represent an average from two separate test runs, necessitated by the tubing's failure during the initial run. This significant difference underscores the enhanced durability and reliability of the SaniSure® tubing in demanding fill/finish operations.
Figure 1. Results of the tubing technical engineering study
Discussion
Contract manufacturers engaged in fill/finish services require robust equipment capable of maximizing fill counts without compromising performance, especially in light of the move toward continuous processing and the increasing demand for biologic drugs. Silicone tubing, integral to these operations, inherently degrades over time, impacting its longevity. However, its composition and manufacturing processes can significantly enhance its performance. The SaniSure® Pharm-A-Clear LH® tubing, specifically developed for critical biopharma applications, is manufactured to exact dimensional tolerances, ensuring prolonged life for peristaltic pumps or pinch valves, as well as high accuracy and purity.
The findings from the tubing technical engineering study affirm that operators using SaniSure®’s Pharm-A-Clear LH® tubing can rely on its stellar performance for up to 18 hours or even across double or triple shifts, depending on operational volume. This extended tubing life not only minimizes the need for frequent changeovers, thereby reducing downtime and associated costs, but also diminishes the risk of manual errors and contamination — a concern specifically addressed in regulatory guidelines such as EU GMP Annex 1.
Moreover, the durability of this tubing reduces spallation, thereby decreasing the likelihood of particulate contamination. Preventing tubing failures is crucial, as exemplified by the issues with the Competitor B product where breakage led to significant product loss and operational halts for deep cleaning and sterilization. Such incidents can result in delays of up to three shift-days, underlining the importance of choosing high-quality, reliable tubing for fill/finish processes.
Maintaining sterility and ensuring the integrity of product and packaging during extensive, high-volume, and high-speed filling operations are crucial for contract manufacturers servicing developers of parenteral drug products. SaniSure®’s Pharm-A-Clear LH® silicone tubing is specially designed for these demanding filling operations. It comes supported by comprehensive quality assurance and documentation that not only meet but often exceed the strictest industry standards.
The results of the recent tubing technical engineering study underscore SaniSure®'s commitment to quality, showcasing decades of expertise in manufacturing both thermoplastic and silicone tubing for bioprocessing applications. This study highlights the company’s robust, data-driven approach to product development and excellence. Drug manufacturers employing SaniSure®'s Pharm-A-Clear LH® tubing can confidently expect to achieve longer operational runs, ensuring product safety while minimizing costs and risks.
SaniSure® is committed to delivering innovative, high-quality solutions that enhance operational efficiency, accuracy, and safety. The company's experts are not only focused on developing single-use products that fulfill customer needs but also provide valuable consultative support, assisting with every aspect of SUT deployment in biopharmaceutical manufacturing settings. This holistic approach ensures that SaniSure® remains a leader in supporting the evolving needs of the biopharmaceutical industry.
References
1. Fill Finish Manufacturing Market - By Product (Consumables {Prefilled Syringes, Vials, Cartridges}, Instruments {Integrated, Standalone}), Application (Parenteral Drug Delivery, Biologics Manufacturing), End-use – Global Forecast (2024 – 2032). Global Market Insights. Mar. 2024.
2. Aseptic Fill Finish Manufacturing Market. Roots Analysis. 2023.
