Industry trends in aseptic processing

Aseptic filling is the last step in the process of manufacturing injectable drug products, and it is critical to preventing contamination, from sterile filtration to closing the filled containers. It’s well documented that the greatest risk to sterile product comes from human intervention in the filling process, giving aseptic processing experts authority to be increasingly critical of manual aseptic technique for injectable drug products. Most recently, regulators have been pushing to minimize operator interventions entirely, when conducting aseptic filling.

We see this noted in a few key expert opinions from regulators, including the following examples:

  • “FDA’s expectation is that the industry will move towards more modern equipment and process control— from manually-intensive processes to automation and moving controls upstream in the process rather than relying on quality control testing of end product to evaluate batch quality.” –Richard Friedman, Deputy Director, Manufacturing Quality, US Food and Drug Administration (FDA) (1)
  • “An ‘advanced aseptic process’ is one in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required and never permitted.” –James Akers, Jim Agalloco, and Russell Madsen (2)
  • “A well-designed aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases.” –US FDA (3)

Separately, we’ve seen an increasing number of pharmaceutical manufacturing applications that require batch sizes of 30 000 units or less – specifically, early-stage clinical trials based on 50 to 100 patients and personalized cell and gene therapies focused on a single patient that require batch sizes of 1000 units or less. We conducted market research that demonstrates this trend (Fig 1) (4) with small-mid sized batches defined as those with batch sizes of 30 000 units or less.

Market research data shows a trend toward smaller batch sizes and personalized therapies

Fig 1. Market research data shows a trend toward smaller batch sizes and personalized therapies (4).

Considerations for automated aseptic processing

When considering aseptic processing technique for the above applications, manufacturers should consider the following points:

Operator error and the risk of contamination

Agalloco and Akers reviewed sources of contamination in cleanrooms between 1986 and 2001, and identified personnel, human error, and non-routine activity as the top three sources (5). While it’s widely understood that humans are the highest source of contamination in a cleanroom, it needs to be said that the risks of human error and non-routine activity is especially high in the aforementioned applications. Facilities focused on development of these applications often have different drug products being produced into different containers, each with their own unique requirements. Having operators trained to deal with this level of variation is difficult, and the chances of making mistakes increases. The repeatability and safety of manual processing under normal circumstances has already been called into question by the FDA. Why employ it when the risks are clearly greater? The same problem of human error exists in manufacturing cell and gene therapies. Patients receiving these therapies have often received alternative treatments without success, so their condition is usually much more fragile and administration cannot be delayed. That’s why shortest manufacturing time is so critical. Risking batch loss to operator error at the filling stage is unacceptable.

The difficulty and cost of integrating and validating aseptic barriers and filling machines from many manufacturers

Having barrier systems and multiple pieces of filling equipment coming from different suppliers creates exponential effort and cost in the procurement, acceptance, qualification, and validation of the overall system. There are multiple parties to chase if something goes wrong, especially in the longer term when service and spare parts will be needed. Manual filling in a biological safety cabinet (BSC) or laminar flow hood (LFH) might seem an easier point of entry for an innovator company or contract development and manufacturing organization (CDMO) establishing aseptic filling capacity. These options would have lower upfront capital costs, but higher longer term operating costs. They add cost, as well as complexity—higher cleanroom classifications, plus more personnel, training, monitoring, and cleaning. It’s only when the time and money have been spent, and complicated procedures have been written, that companies wish they took the isolator path or considered automated solutions. Evaluating investment costs and operational costs when building out your capabilities is critical prior to taking on this burden.

Manual operations raise the cost and failure rate of personalized medicines

Aside from investment recovery, one of the main reasons autologous cell and gene therapies cost so much is that manufacturing them can be highly manual. Lopes, Sinclair, and Frohlich modelled autologous cell and gene therapy production costs, examining how different approaches to manufacturing divided expenses (6,7). They also looked at whether these approaches could impact the efficacy of the therapy. Their model found that highly manual operations would have labor costs up to 50% of the cost of goods sold (COGS), whereas partially automated or automated operations range between 18% to 26%. Simultaneously, their models predicted failure rates of 10% for manual processes and only 3% for automated models, due to the 3.3-fold reduction in the number of manual interventions in the process. The authors’ suggestion was that automated systems needed to exist that would remove bottlenecks via parallel processing. This suggestion points to the need for equipment standardization as a path to reducing manufacturing costs of personalized medicines. If the market prices of autologous therapies remain as-is, it will be difficult to realize their full commercial value. Cost of goods needs to come down for prices to be lower, which would lead to their broader usage. The industry will need to go through a wave of automation as it did during the first wave of biopharma drugs, standardizing around processes and automated equipment. Surrendering to manual processing as the go-to method will affect costs, efficacy, and the safety of patients.

Gloveless isolators give way to automated aseptic processing

It’s taken some time to make the point that manual aseptic processing is probably the last resort, rather than the best approach for small batch filling applications. So what does Cytiva propose as a solution? And how can we solve the issues of utilization rates, production inflexibility, changeover and decontamination times, and capital costs, which are often challenges of small batch applications?

For us, it starts with our Microcell™ vial filler. Cytiva explicitly developed this aseptic filling machine as a replacement for manual filling inside a BSC, LFH, or isolator. It was developed with “something for everyone” in mind—an aseptic filling machine that many companies could use, whether they were a CDMO looking to be agile or an innovator trying to develop manufacturing capacity. Whatever the type of organization, the costs of phase I/II trials for personalized medicines can be driven down.

The Microcell™ vial filler was designed to meet customer utilization rate expectations, with the ability to fill at least four different drug products in eight hours, totalling 1200 units. A 15 min vapour-phase hydrogen peroxide decontamination and aeration cycle supports a 6-log kill of a biological indicator, and can be performed post-fill for viral deactivation. Single-use flowpaths, product bags, and filling needles prevent cross-contamination. The Microcell™ vial filler has tool-less changeover for vial sizes from 2R to 50R and fill volumes from 1 to 50 mL. Recipe-driven automation supports the manufacturing of many different drug products.

Each Microcell™ vial filler is a standard product, allowing rapid scale-out for additional capacity. This will be especially useful as cell and gene therapies are commercialized and need more scale. It requires 13 m2 (140 sq. ft.) of Grade C or D space, with only minimal supporting utilities of power, compressed air, and an external exhaust (no upper plenum or connection to air handling systems). The use of pre-sterilized, nested vials and press-fit vial closures with industry standard stoppers eliminates the need for washing and depyrogenation equipment.

Need help with your small batch application? We’re here for you

The Cytiva Microcell™ vial filler is a vial-only filler supporting the many early-stage clinical drugs and cell and gene therapies delivered in vials, and the core of the machine—its isolator, decontamination, and automation systems—form a platform applicable to other aseptic processing applications should your needs require.

If you have small batch aseptic processing requirements, please contact us to have a discussion around delivering an automated aseptic filling process that is repeatable, cost-effective, and safe. With 20 and counting Microcell™ vial fillers sold for GMP production, we understand your aseptic filling needs. Let Cytiva eliminate barriers and help you isolate better.

References

  1. Is pharma getting worse at manufacturing? Pharmafile. https://pharmafile.com/features/fda-interview-pharma-getting-worse-manufacturing/. Published September 29, 2010. Accessed November 2024.
  2. Akers J, Agalloco J, Madsen R. What is Advanced Aseptic Processing? Pharm. Manuf. 2006;4(2):25-27.
  3. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice. US Food and Drug Administration (FDA). September 2004. Accessed November 2024. https://www.fda.gov/media/71026/download
  4. Aseptic filling market assessment, for Cytiva. Boston Consulting Group. December 8, 2023.
  5. Agalloco J, Akers J. Aseptic processing: A vision of the future. Pharm. Tech. 2005;29:s16-s23.
  6. Lopes AG, Sinclair A, Frohlich B. Cost Analysis of Cell Therapy Manufacture: Autologous Cell Therapies, Part 1. BioProcess International. https://www.bioprocessintl.com/cell-therapies/cost-analysis-of-cell-therapy-manufacture-autologous-cell-therapies-part-1. Published March 27, 2018. Accessed November 2024.
  7. Lopes AG, Sinclair A, Frohlich B. Cost Analysis of Cell Therapy Manufacture: Autologous Cell Therapies, Part 2. BioProcess International. https://www.bioprocessintl.com/cell-therapies/cost-analysis-of-cell-therapy-manufacture-autologous-cell-therapies-part-2. Published April 20, 2018. Accessed November 2024.