Innovations and Trends in Aseptic Manufacturing Processes

In 2022, the number of newly approved biologic drugs outpaced that of small molecules for the first time (1). Notably, almost a third of the new approvals comprised novel modalities, such as cell and gene therapies, antibody–drug conjugates, and bispecific proteins. In fact, a report forecasted biologics sales to exceed that of small molecules drugs by 2027 (2). The steady rise in popularity of gene therapies and other biologics is the underlying reason for the growing importance of aseptic manufacturing processes in the biopharmaceutical industry.

Traditional small-molecule drugs are chemically derived and manufactured using terminal sterilization, in which the drug product in its primary packing is sterilized using high heat, radiation, or filtration. In contrast, biologics—which include gene therapies, transplant tissue, recombinant proteins, and monoclonal antibodies—are composed of tissue, cells, nucleic acids, proteins, sugars, and more, which degrade and lose potency when subjected to the harsh conditions of terminal sterilization.

Gene therapies deliver DNA, RNA, or ribonucleic proteins into the living cells of a patient to correct a specific genetic variation or introduce a therapeutic gene. Delivery of genetic material can be achieved in several ways, but is commonly achieved by using viral vectors, such as adeno-associated viruses or lentiviruses, which cannot withstand terminal sterilization.

At the same time, gene therapies are administered parenterally (i.e., injected into the body intravenously, intramuscularly, or subcutaneously). Parenteral drug delivery bypasses the body’s natural defenses against pathogens, thereby increasing the risk of infection to the patient, which necessitates the more complex process of aseptic manufacturing of viral vector-based gene therapies to ensure their efficacy, while being safe to inject into patients.

Gene therapies also pose an additional challenge. Traditional biopharmaceutical manufacturing is built around the “one product, one facility” paradigm. Here, high-volume stainless steel bioreactors produce a single drug product on a large scale at a dedicated manufacturing facility. However, due to the personalized nature of gene therapy, as well as the size of the patient population for which they are intended, this landscape is undergoing a transformation as smaller, adaptable, multi-product manufacturing gains prominence. Here, the author discusses innovations and trends in aseptic manufacturing processes, with a focus on considerations to produce viral vectors for gene therapy.

Aseptic manufacturing processes

According to the guidance issued by FDA (3), in an aseptic process, the drug product, any excipients, the container, and closure are individually sterilized using appropriate methods, and then put together in a high-quality, sterile environment. This step, referred to as sterile fill/finish, is done in a cleanroom and often uses special equipment that is self-contained in a sterile environment. Because it is impossible to sterilize the drug product in its final container, it is crucial that the containers be filled and sealed in a highly controlled environment, which is constantly monitored for the presence of microbes and particulate matter, and ensures the appropriate temperature, humidity, air pressure, and ventilation.

Despite these measures, it is well established that operators are the predominant source of microbial contamination in aseptic processes, accounting for an estimated 80–90% of common contamination sources (4). Aseptic control is especially critical in gene therapy production, because there are more manual manipulations in these processes compared to traditional biologics (often left over from processes developed in an academic lab), making them more vulnerable to microbial ingress. Developing safe, reliable, and scalable manufacturing processes for gene therapy remains a key limitation to their clinical application. Central to such processes are the use of closed systems that incorporate single-use technologies (SUTs).

Closing the loop on stainless steel bioreactors with SUTs

As the name suggests, a closed system is one in which the product is physically isolated from the surrounding environment and personnel. Materials may be added into, or removed from, the system at designated control points in a way that does not expose the product to the environment.

Achieving 100% closure has long been a coveted goal for biomanufacturing. A fully closed aseptic manufacturing process typically includes:

• Closed bioreactors—including sealed and sterile chambers, preventing any contact between the cell culture and the external environment
• Closed media and reagent delivery systems—including the use of sterile and disposable bags or containers with integrated tubing and connectors that allow for aseptic transfer of fluids
• Closed sampling and monitoring systems—including sterile connectors or sampling ports that enable aseptic sampling, as well as integrated sensors and probes for in-process monitoring of parameters such as pH, dissolved oxygen, and temperature
• Closed harvest and purification systems—including closed filtration systems, centrifuges, or other media separation techniques
• Closed formulation and fill/finish systems—including sterile, disposable, and closed filling equipment with integrated sealing mechanisms
• Closed waste management systems
• Integrated control and automation systems
• SUTs—sterile, disposable, ready-to-use equipment and consumables such as media and buffer bags, filters, tubing and connectors, chromatography columns, and bioreactors.

Beyond preventing the potential loss of product due to contamination, closed systems that use SUTs offer several other advantages that are extremely beneficial in the context of gene therapy manufacturing, such as:

1. Flexible facility—Closed systems can be operated in various environments, including aseptic cleanrooms, as well as controlled-not-classified (CNC) environments. CNCs, in particular, eliminate the need for airlocks and extensive gowning, enabling a less segregated facility that can support the manufacture of smaller batches of multiple products in parallel. Small-batch aseptic processes are integral to the manufacture of personalized treatments such as gene therapies.
2. Scalability—Construction of manufacturing facilities employing reusable stainless-steel equipment can take four to five years, with additional time required for plant validation (5), making them slow to scale. In contrast, closed systems using SUTs offer a plug-and-play solution, which allows a facility to be up and running in a matter of months, especially when leveraging prefabricated, modular cleanrooms. Modular manufacturing facilities offer the flexibility to scale as needed to meet clinical trial needs or market demands.
3. Speed of operation—A closed system minimizes the need for extensive operator involvement and streamlines the overall procedure. If the closed system is implemented using SUTs, time savings are further amplified due to reductions in setup, product changeover, line clearance, cleaning, and validation. In fact, the elimination of time-consuming, clean-in-place and steam-in-place operations needed with stainless-steel equipment is a key driver for the rapid uptake of SUTs (6).
4. Capital and operating cost—A traditional biomanufacturing facility typically requires an upfront capital investment of more than $450 million. This poses significant risk during clinical trials and initial commercial production and can be especially daunting for startups and small biopharmaceutical companies. Closed systems that utilize SUTs have comparatively lower operating costs through energy savings from the elimination of airlocks, environmental monitoring and cleaning, reduction in gowning, and more. Case studies comparing the costs of facilities that use SUTs with those that use stainless-steel equipment demonstrate approximate capital and operating expenditure savings of up to 70–25%, respectively (7).

Implementing a fully closed system is, however, technically challenging, and many biopharmaceutical companies partner with a contract development and manufacturing organization (CDMO). However, many CDMOs, such as FUJIFILM Diosynth, BioCentriq and others, often opt for a functionally, rather than fully, closed system, which has limited exposure to the processing environment. A functionally closed system may be routinely opened for manual intervention and returned to a closed state by sterilization before process use. Such systems are easier to engineer, but more prone to contamination due to its reliance on the operator to ensure sterility.

In contrast, Matica Bio’s facility in College Station, Texas is a GMP-certified, 100% fully (physically and functionally) closed manufacturing system that was built using modular, prefabricated cleanrooms.

Conclusion

While gene therapies hold immense promise in revolutionizing healthcare by addressing the underlying genetic causes of diseases, their successful translation to widespread clinical application hinges on the ability to produce them in a manner that is reliable, scalable, and economically viable. The integration of modular facilities and closed processing have emerged as a compelling choice for CDMOs in the gene therapy arena, minimizing the risk of contamination, and enabling efficient workflows, rapid scaling, and greater flexibility.

References

1. Senior, M. Fresh from the Biotech Pipeline: Fewer Approvals, but Biologics Gain Share. Nat Biotechnol. Jan. 9, 2023. 41 (2) 174–182. https://doi.org/10.1038/s41587-022-01630-6.
2. GlobalData. Looking Ahead to 2022 – The Future of Pharma; Edition; GlobalData. April 2021.
3. FDA. Guideline on Sterile Drug Products Produced by Aseptic Processing, 2004 (accessed Sep 1, 2023).
4. PDA. PDA Technical Report No. 22 (2011 Revision). Process Simulation Testing for Aseptically Filled Products. 2011 (accessed Sep 1, 2023).
5. Samaras, J.; Micheletti, M.; Ding, W. Transformation of Biopharmaceutical Manufacturing Through Single-Use Technologies: Current State, Remaining Challenges, and Future Development, Annual Review of Chemical and Biomolecular Engineering, 2022, 13:73-97.
6. Morrow J.K.; Langer E.S.; Rise of Single-use Bioprocessing Technologies: Dominating Most R&D and Clinical Manufacture. Am. Pharm. Rev. 2020, 23(1):38–41.
7. Ravisé A.; Cameau E.; De Abreu G. et. al. Hybrid and Disposable Facilities for Manufacturing of Biopharmaceuticals: Pros and Cons. Adv Biochem Eng Biotechnol. 2009, 115, 185-219. doi: 10.1007/10_2008_24.

About the Author

Brian Greven is senior director of Quality & Validation at Matica Bio.

Article Details

BioPharm International

Volume 36, No.10

October 2023

Pages 21-23

Citation

When referring to this article, please cite it as Greven, B. Innovations and Trends in Aseptic Manufacturing Processes. BioPharm International 36 (10) 2023 21-23.