Sterile drug product manufacturing is a complex yet vital aspect of the pharmaceutical industry, essential for producing safe and effective medications. Over time, advancements and innovations in this field have revolutionized manufacturing processes, significantly improving product quality, efficiency, and safety.
This article explores key developments in sterile drug product manufacturing, from traditional sterile fill-finish methods to cutting-edge robotic technologies that address regulatory challenges, help ensure patient safety, and highlight the industry's commitment to continuous improvement.
Traditional Sterile Drug Product Manufacturing
Aseptic processing involves sterilizing components and equipment and controlling environmental conditions to prevent microbial contamination during drug product formulation and filling. Historically, sterile drug manufacturing has relied on aseptic processing techniques such as filtration and terminal sterilization to eliminate or control potential microbial contamination.
There are two conventional means of accomplishing these goals, the first being sterile filtration. Sterile manufacturing of monoclonal antibodies (mAbs) and other biologic modalities relies on effective and efficient filtration processes to remove microorganisms and particles that could compromise drug product purity. Sterilizing grade filters with tiny pores, typically ranging from 0.1 to 0.2 micrometers in size, are used in manufacturing sterile drug products, and play a pivotal role in assuring final product sterility.
The second method is terminal sterilization, which refers to the process of sterilizing a drug product, typically in its final container, to eliminate any microorganisms that may be present, thereby ensuring its safety, efficacy, and stability. This process is typically performed using methods such as steam, radiation, or chemical sterilization. The precise method used depends on the drug product's sensitivity; for example, gamma radiation may be used for drug products that cannot withstand heat. It is important to note that products terminally sterilized should not be filled aseptically alone. They can, however, be processed aseptically if terminally sterilized afterward. Buffers, placebos, and some small molecules would be representative of such products suitable for terminal sterilization.
Novel Aseptic Techniques
From isolator technology to restricted access barrier systems (RABS), novel aseptic techniques contribute to maintaining product integrity, safety, and compliance with global regulatory standards. By separating operators from the product at all times, inline monitoring and control systems further improve aseptic processing environments.
Among the significant innovations in sterile drug manufacturing has been the adoption of single-use technologies (SUTs) to replace conventional reusable stainless-steel vessels and processing lines. Single-use systems, including disposable bags, filters, tubing, and connectors, have gained popularity due to several factors.
For starters, single-use systems require little or no cleaning, and replacing them at the end of each batch saves time and money involved with cleaning and validation requirements. They are also flexible and adaptable, quickly, and easily modified to fit each process and scale requirements, and minimize validation costs by allowing safe and expedient changeover. A related benefit is that single-use systems also save time since they remove cleaning and validation or verification periods. This can improve batch turnaround times and, ultimately, help reduce time to market.
And since they are replaced after each batch, single-use technologies also offer reduced risk of product cross-contamination. Finally, they create a sealed barrier that separates the product from operators, de-risking the process and enhancing sterility.
Although SUTs are gaining momentum, the technology ideal for a specific sterile manufacturing application depends on various considerations, batch size chief among them. In many cases, biopharmaceutical companies and CDMOs are reaping the benefits of implementing hybrid approaches across their global sterile fill-finish manufacturing networks. For instance, while SUTs are possible up to 2,000L, bags at that size are expensive and have a comparably elevated known failure rate. Considering this, SUTs tend to be compelling options at batch sizes up to 500 to 600L, but less so above this volume. Another point to note is that, compared with stainless steel vessels, SUTs do add some recurring batch costs that are otherwise unnecessary – most prominently the bags themselves.
In recent years, advancements in another novel technique, advanced aseptic processing, have been incorporated to enhance the sterility assurance of drug products. Such technologies focus on minimizing human interventions, automating processes, and optimizing cleanroom designs.
For one, closed systems fall under this category. Closed systems aim to minimize the exposure of drug products to the environment and humans, reducing the risk of contamination. Isolators and RABS provide physical barriers, ensuring a sterile environment during drug manufacturing processes. Isolators utilize glove ports to support necessary interventions. Of course, these gloves must be tested regularly and do represent a potential point of failure or risk.
Increasingly, robotics and automation also are being utilized. Integrating robotics and automation into aseptic processing reduces human interventions, lowering the risk of microbial contamination. Automated systems for vial filling, syringe filling, and loading/ unloading lyophilization systems enhance precision and efficiency.
Gloveless robotic isolator-filling technologies also are becoming more popular. With no glove ports, validated robots perform all operations within a closed isolator system. Using ready-to-use (RTU) components and integrating filling and handling robotics within gloveless isolator technology platforms further reduces the risk of microbial contamination and particulate generation, providing a higher quality, more sterility-assured drug product. Having a robust and validated robotic system is critical because, if an intervention that the robot cannot perform is required, the batch will unfortunately be aborted.
Advancements in automation and robotics are revolutionizing sterile f ill-finish processing. From vial loading to stoppering, advanced robotics are streamlining and enhancing the efficiency of sterile fill finish operations with reduced human interventions, minimizing contamination risks while optimizing production speed and time-to-market to provide life-changing therapies to patients.
Regulatory Landscape and Compliance
The regulatory landscape for sterile drug product manufacturing is stringent, reflecting the critical importance of ensuring product safety and efficacy. Regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) continue to evolve guidelines and standards to keep pace with technological advancements.
In Europe, the Annex 1 Revision (EudraLex Volume 4 Annex 1) of the EU Good Manufacturing Practice (GMP) guidelines outlines requirements for sterile medicinal products. The revision of Annex 1, which became effective in August 2023, focuses on addressing new technologies and concepts – including Pre-Use Post Sterilization Integrity Testing (PUPSIT), the use of closed systems (RABS and isolators), and automation – and reinforces quality risk management principles and the requirement for contamination control strategies. In the United States, the FDA provides comprehensive guidance on aseptic processing covering various aspects, including facility design, environmental monitoring, and process validation.
While both the FDA guidance and EU Annex 1 address sterile drug production, they may differ in specific details and approaches. Manufacturers must carefully consider and align their practices with the relevant guidelines to ensure the safety and quality of sterile products comply with corresponding geographies. While there are naturally significant overlap and mutual recognition, there are still some differences in expectations and regulatory requirements.
Quality by Design (QbD) and Process Analytical Technology (PAT)
Quality by Design (QbD) and Process Analytical Technology (PAT) are regulatory initiatives that have influenced sterile drug product development and manufacturing. These approaches emphasize a systematic understanding of processes and use real-time monitoring to ensure product quality. QbD involves developing and controlling manufacturing processes to ensure the desired product quality. By identifying Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs), manufacturers can optimize processes and enhance the overall quality of sterile drug products.
Meanwhile, PAT implementation incorporates real-time monitoring and control of critical process parameters during manufacturing. Techniques such as near-infrared spectroscopy, Raman spectroscopy, and mass spectrometry provide in-process analysis, allowing for immediate adjustments to maintain target product quality. By integrating PAT into aseptic processing systems, manufacturers can gain deeper insights into process variables and optimize production parameters to improve efficiency and product quality. PAT-enabled processes enable faster process development and validation, leading to expedited product commercialization.
Environmental Monitoring and Control
Maintaining a controlled and clean environment is paramount in sterile drug product manufacturing. Advances in environmental monitoring and control systems contribute to the prevention of microbial contamination and the assurance of product quality.
Continuous, real-time environmental monitoring of critical parameters, such as non-viable and viable particulate counts and microbial levels, allows for immediate corrective actions, reducing contamination risk. Advanced monitoring systems provide a more comprehensive understanding of cleanroom conditions. Similarly, innovations in barrier technologies, including isolators and RABS, contribute to the creation of controlled environments that minimize the risk of microbial contamination from manufacturing operators. These technologies offer enhanced protection for both personnel and drug products.
While manufacturing a safe, sterile drug product for patient use is the primary objective, the impact of operations on the environment ON-DEMAND WEBINAR is becoming a greater area of focus within the industry. Considering environmental monitoring and impact, biopharmaceutical manufacturers and partnering CDMOs are working to incorporate greener initiatives into sterile fill-finish processes, including eco-friendly packaging materials and more energy-efficient manufacturing facilities.
Conclusion
Advancements and innovations in sterile drug product manufacturing have transformed the pharmaceutical industry, enabling the production of safer and more efficient life-changing therapies. As the industry moves forward, aseptic liquid filling, automation, and environmental considerations will continue to shape the landscape of sterile fill-finish, with a focus on adherence to evolving regulatory standards. Sterile fill-finish equipment and manufacturing environments must advance to meet the “current” in “c” GMP.
The commitment to patient safety and product efficacy remains at the forefront of these advancements, driving continuous improvement in sterile drug product manufacturing. As technologies mature and regulatory frameworks adapt, the industry will undoubtedly witness further breakthroughs, ensuring the delivery of high-quality biologics and sterile injectables to patients around the world.
Author Details
Shawn Cain, SVP Development & Manufacturing and General Manager, PCI Pharma Services- Bedford, NH.
Publication Details
This article appeared in Pharmaceutical Outsourcing: Vol. 25, No.3 July/Aug/Sept 2024Pages: 8-11