The Future of Sterility: Advancements and Innovations in Sterile Drug Product Manufacturing 

Sterile drug product manufacturing is complex and plays a crucial role in the pharmaceutical industry, ensuring the production of safe and effective medications for patient use.

Over the years, the advancements and innovations in this field have transformed the manufacturing processes, enhancing product quality, efficiency, and safety. This article explores the key developments in sterile drug product manufacturing, from traditional methods to cutting-edge robotic technologies, addressing regulatory challenges, ensuring patient safety and highlighting the industry’s commitment to continuous improvement. 

Traditional Sterile Drug Product Manufacturing 

Aseptic processing involves the sterilisation of components, equipment, and the control of the environment to prevent microbial contamination during drug product formulation and filling. Historically, sterile drug manufacturing relied on aseptic processing techniques such as filtration and terminal sterilisation to eliminate or control potential microbial contamination. 

  • Sterile Filtration: Sterile manufacturing of monoclonal antibodies (mAbs) and other biologic modalities relies on effective and efficient filtration processes to remove micro-organisms and particles that compromise drug product purity. Sterilising-grade filters with extremely small pores, typically ranging from 0.1 to 0.2 micrometres in size are used in the manufacturing of sterile drug products and play a pivotal role in assuring final product sterility. 
  • Terminal Sterilisation: Terminal steri-lisation refers to the process of steri-lising a drug product, typically in its final container, to eliminate any micro-organisms that may be present and ensure its safety, efficacy and stability. This process is typically performed using methods such as steam, radiation, or chemical sterilisation. The 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 highlight that if a product can be terminally sterilised, it should not be filled aseptically alone. It can be processed aseptically if it is terminally sterilised after. Buffers, placebos and some small molecules would be representative of such products that require terminal sterilisation.

Novel Aseptic Techniques

From isolator technology to restricted access barrier systems (RABS), these innovations contribute to maintaining product integrity, safety and compliance with global regulatory standards. Inline monitoring and control systems further improve the aseptic processing environment, by separating operators from the product at all times.

1. Single-Use Technologies 

One of 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 also gained popularity due to: 

  • Little or no cleaning required – replacing at the end of each batch, saves time and money involved with cleaning and validation requirements. 
  • Flexible and adaptable – single-use products can be quickly and easily modified to fit each process and scale requirements. They also allow for a safe and quick transition of changes, minimising validation costs. 
  • Time saving – Removing cleaning and validation or verification periods, helps reduce time to market and improves batch turnaround times. 
  • Reduced risk of product cross-contamination – single-use products are replaced after each batch, which eliminates the risk of cross-contamination between products. 
  • Creates a sealed barrier that separates the product from the operators, de-risking the process and enhancing sterility. 

Although SUTs are gaining momentum, which technology is best for sterile manu-facturing is dependent on various considerations such as batch sizes. In many cases, biopharmaceutical companies and CDMOs alike are reaping the benefits of implementing hybrid approaches across their global sterile fill-finish manufacturing networks. For instance, SUTs are possible up to 2,000 litres, however, bags at that size are expensive and do have a known failure rate. SUTs are valuable up to 500 to 600 litres but less so above this size. Another point to note is that SUTs do add some recurring batch costs that are not necessary if you are manufacturing commercial batches. Then it is just processing and energy costs. 

2. Advanced Aseptic Processing 

In recent years, advancements in aseptic processing techniques have enhanced the sterility assurance of drug products. New technologies focus on minimising human interventions, automating processes, and optimising cleanroom designs. 

  • Closed Systems: Closed systems aim to minimise the exposure of drug products to the environment and humans by reducing the risk of contamination. Isolators and RABS provide physical barriers, ensuring a sterile environment during drug manufacturing processes. Isolators utilise glove ports to support necessary interventions. These gloves need to be tested regularly and do represent a potential point of failure/ risk. 
  • Robotics and Automation: Integrating robotics and automation into aseptic processing reduces human interventions, lowering the risk of microbial conta-mination. Automated systems for vial filling, syringe filling, and loading/ unloading lyophilisation systems enhance precision and efficiency. 
  • Gloveless Robotic Isolator Filling Technology: 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 an increased quality and sterility assured drug product. Having a robust and validated robotic system is critical, as if there is an intervention required that the robot cannot perform, then the batch will be aborted.

Advancements in automation and robotics are revolutionising sterile fill-finish processing. From vial loading to stoppering, advanced robotics are streamlining and enhancing the efficiency of sterile fill-finish operations with reduced human interventions, minimising contamination risks, while optimising production speed and time 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 the technological advancements. 

  • 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 Sterilisation Integrity Testing (PUPSIT), the use of closed systems (RABS and isolators), automation, and reinforces quality risk management principles and the requirement for contamination control strategies. 
  • FDA Guidance on Sterile Drug Products Produced by Aseptic Processing: 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 the geographies they intend to market their products. While there is some 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 emphasise a systematic understanding of the processes and use real-time monitoring to ensure product quality. 

  • QbD Principles: QbD involves designing and controlling manufacturing processes to ensure the desired product quality. By identifying critical process parameters (CPPs) and critical quality attributes (CQAs), manufacturers can optimise processes and enhance the overall quality of sterile drug products. 
  • PAT Implementation: PAT 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 the target product quality.

Environmental Monitoring and Control 

Maintaining a controlled and clean environ-ment 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. 

  • Real-Time Environmental Monitoring: Continuous, real-time monitoring of critical parameters such as non-viable and viable particulate counts and microbial levels allows for immediate corrective actions, reducing the risk of contamination. Advanced monitoring systems provide a more comprehensive understanding of cleanroom conditions. 
  • Barrier Technologies: Innovations in barrier technologies, including isolators and RABS, contribute to the creation of controlled environments that minimise 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 is becoming a greater area of focus within the industry. Considering environmental monitoring and impact, biopharmaceutical manufacturers and their partnering CDMOs are working to incorporate green initiatives into their sterile fill-finish processes, from using eco-friendly packaging materials to 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. It is imperative that sterile fill-finish equipment and manufacturing environments advance to meet the “current” in cGMP. 

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.

The Future of Sterility:  Advancements and Innovations in Sterile Drug Product Manufacturing  with Shawn Cain | As seen in IPI | April 2024


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