Manual aseptic processing needs to end
This blog is a response to the article “Manual Aseptic Processing: The Last Resort or the Best Approach?” by Brendan Fay of the consulting firm IPS.
Manual aseptic processing is definitely not the best approach. It’s currently the last resort, but Vanrx would go a step further and suggest that manual aseptic processing should end. The technologies and process understanding exist to do away with operator-driven aseptic technique.
So it goes without saying that we disagree with Mr. Fay’s assertions. We shake our heads at the suggestion that the most cutting-edge therapies—the ones erasing terminal cancer or giving children their sight back—should be left to a human operator for the crucial step of aseptic filling.
And we are not the only ones saying this.
Aseptic processing experts have been highly critical of manual aseptic technique for filling injectable drug products. Regulators have been pushing to minimize operator interventions.
Here are some of those expert opinions:
“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.”1
– Richard Friedman, U.S. FDA Office of Manufacturing Quality, Deputy Director for Science and Regulatory Policy
“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.”2
– James Akers, Jim Agalloco & Russell Madsen
“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.”3
– U.S. Food and Drug Administration
Mr. Fay states that there are an increasing number of pharmaceutical manufacturing applications requiring batch sizes of 1,000 units or less. The examples provided are early-stage clinical trials based on 50-100 patients, and personalized cell & gene therapies focused on a single patient. The article disqualifies current automated filling systems for these applications because of long changeover and decontamination times, complicated change parts, capital cost, and inflexibility for different container types. His key metric is an 80% time utilization target for the equipment. If this metric cannot be met, other methods should be considered.
The solution proposed by Mr. Fay is manual aseptic technique. The article proposes that for small batches, this is the best way of achieving small batch flexibility for multiple container types (vial, syringes, cartridges, IV bags or custom containers). This activity would occur using a biosafety cabinet (BSC), laminar flow hood (LFH) or isolator, with manual pipetting or tabletop filling and capping / stoppering machines employed.
Vanrx’s counter proposal is that manual aseptic processing is a regressive practice that is too risky and inefficient to be applied to cutting-edge medicines. Precisely controlled, highly automated aseptic processes within gloveless isolators is the best option for small batch aseptic filling applications.
Three reasons to do away with manual aseptic processing
Manual aseptic processing is not acceptable for today’s complex therapeutics for three key reasons, focused on contamination, drug efficacy, efficiency and cost.
1. 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 dirtiest thing in a cleanroom, it needs to be said that the risks of human error and non-routine activity is especially high in the applications described by Mr. Fay. These are facilities with 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 FDA. Why employ it when the risks are greater?
The same problem of human error exists in manufacturing cell & gene therapies. Patients receiving these therapies have been through other treatments without success, so their condition is fragile and administration cannot be delayed. That’s why vein-to-vein manufacturing time is so critical. Risking batch loss to operator error at the filling stage is unacceptable. We covered filling requirements for cell and gene therapies in our white paper Aseptic Filling for Personalized Medicines.
2. The difficulty and cost of integrating and validating aseptic barriers and filling machines from many manufacturers
The topic of aseptic barrier systems and the obstacles to implementing them for aseptic filling has been covered in one of our other blog posts.
Mr. Fay describes three barrier possibilities—BSCs or LFHs installed in a Grade B cleanroom or a glovebox isolator in a Grade C or D cleanroom. 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 where service and spare parts will be needed.
Manual filling in a BSC or LFH might seem an easier point of entry for an innovator company or CMO 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 has been spent, and complicated procedures are written, that companies wish they took the isolator path or considered automated solutions.
3. 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 is still highly manual.
Lopes, Sinclair and Frohlich modelled autologous cell & gene therapy production costs, examining how different approaches to manufacturing divided expenses. They also looked at whether these approaches could impact the efficacy of the therapy.
Their model found that highly manual operations would have labour costs up to 50% of the cost of goods sold (COGS), whereas partially automated or automated operations range between 18-26%. Simultaneously, their models predicted failure rates of 10% for manual processes and only 3% for automated models, due to the 3.3x reduction in the number of manual interventions in the process.6
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 harm patients.
Gloveless robotic isolators to replace manual 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 is our proposed solution? Does it resolve Mr. Fay’s issues of utilization rates, production inflexibility, long changeover and decontamination times, complicated change parts, and capital cost? Yes, it does.
It starts with the Vanrx Microcell Vial Filler. Vanrx explicitly developed the machine as a replacement for manual filling inside a BSC, LFH or isolator. It was envisioned as a “Coke machine for biotech”—something that every company could use, whether they were a CMO looking to be agile, or an innovator trying to develop manufacturing capacity. With either type of organization, the costs of Phase I/II trials or personalized medicines can be driven down.
The Microcell easily meets Mr. Fay’s 80% utilization rate, with the ability to fill at least four different drug products in an 8-hour shift (including lunch break), totalling 1,200 units. A 15-minute 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 flow paths, product bags and filling needles prevent cross-contamination. The Microcell has tool-less changeover for vial sizes from 2R-50R and fill volumes from 1-50 mL. Recipe-driven automation supports the manufacturing of many different drug products.
Each Microcell 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.
Contact us with your small batch application
The Vanrx Microcell is a vial-only filler supporting the many early-stage clinical drugs and cell and gene therapies delivered in vials.
The core of the Microcell—its isolator, decontamination and automation systems—form a platform applicable to other aseptic processing applications. If you have small batch aseptic processing requirement we would urge you to contact Vanrx via the form below to have a discussion around delivering an automated system and process that is repeatable, cost-effective and safe.
- Pharmafile. “Is pharma getting worse at manufacturing?” Published: 29/09/2010. Accessed: 25/08/2018. URL: http://www.pharmafile.com/news/fda-interview-pharma-getting-worse-manufacturing
- Akers, J, Agalloco, J, Madsen, R. What is Advanced Aseptic Processing? Pharm. Manuf. 2006: 4(2) 25 – 27.
- Food and Drug Administration. Guideline on Sterile Drug Products Produced by Aseptic Processing (FDA, Rockville, MD, 2004).
- Agalloco, J & Akers, J, , Madsen, R. Aseptic processing: A vision of the future? Pharm. Manuf. 2006: 4(2) 25 – 27.
- Agalloco, J & Akers, J. (2005). Aseptic processing: A vision of the future. Pharm. Tech. 29. s16-s23.
- Lopes, A.G., Sinclair, A. & Frohlich, B. Published: Published: 27/03/2018 & 20/04/2018 Accessed: 25/08/2018 URLS: http://www.bioprocessintl.com/manufacturing/cell-therapies/analysis-cost-of-cell-therapy-manufacturing-autologous-cell-therapies-part-1/ and http://www.bioprocessintl.com/manufacturing/cell-therapies/cost-analysis-of-cell-therapy-manufacturing-autologous-cell-therapies-part-2/