Martin Muffler senior process engineer at CRB looks at risk mitigation in aseptic production with a view to future developments.
The European Pharmacopoeia’s definition is simple and comprehensible:
“The aim of production under aseptic conditions is to preserve the sterility of a preparation composed of sterilised components. This means that the raw materials necessary for production, including primary packaging, should be sterilised before aseptic further processing, provided that this is possible, and no contamination may occur during production.”
The greatest risk of contamination in aseptic production comes from humans. Reduced number of interventions in critical zones leads to higher product safety.
The operator as a source of contamination
This was recognised early on and the processes have been further developed and improved in recent years or decades with special attention to the rooms, gowning of the employees, the training of the employees and the physical and microbiological monitoring.
A contamination-free filling is proven by a variety of measurements such as microbiological monitoring, physical monitoring, monitoring of air velocities and smoke studies in the cleanroom. Improvements were achieved through changes in cleaning and disinfection cycles, division of the production rooms into separate zones and separate air locks for employees and materials.
The entire filling process is validated by periodic media fill. Here, all interventions during the past production period are simulated and evaluated back to the last successful media fill. Here it becomes clear what risks can emanate from an intervention or an incorrect assessment of the intervention. In the event of contamination during media fill, all batches are potentially affected. This not only represents a very high risk for drug and patient safety but also a very high business risk for the company.
The evaluations are time-consuming, cost-intensive and due to the high number of measurements, there is an additional risk of a false positive result due to human error. This is followed by intensive time-consuming risk assessments with a worst case of having to discard the filled product.
Microorganisms are not visible
Microbiological contamination only becomes visible days after production through the incubation of the culture media.
The conclusion is obvious, how can interventions be avoided and how can the risk be minimised?
A major milestone in reducing product risk has been achieved through the use of closed restricted access barrier systems (RABS) and Isolator technology. These systems allow the separation of the product from the intervening operator.
Annex 1 of the EU GMP Guide "Manufacture of Sterile Medicinal Products" regulates the manufacture of sterile medicinal products in Europe. On February 20, 2021, the European Commission published a second draft revision of the document after 2017.
Chapter 4 of the new draft, which deals with the design and qualification of premises contains very strict requirements. The draft elevates RABS and isolators as the primary means when it comes to minimising microbial contamination from direct human intervention in the critical zone. The draft is very clear in describing the requirement. "Any alternative approaches to the use of RABS or isolators should be justified".
Therefore, companies must inevitably and intensively deal with the topic of containment. Presumably, good reasons are needed for not considering the use of containment in future pharmaceutical production. Containment goes from a "can" to a "must".
The pharmaceutical world is changing. New active ingredients, biotherapeutics, ATMPs, ADCs are leading to the future of medicine. Personalised medicine could promise a cure or relief with only a few drug doses. This will almost certainly lead to smaller batch sizes. Also, the future APIs will be time and cost-intensive to produce, which will further increase the business risk on the process of fill and finish.
But as recent events have shown, even large batches are likely to continue to be of great importance in the future. The fight against the Covid-19 pandemic is certainly surprising here, who would have thought of such a high demand for vaccine doses worldwide before the outbreak of the pandemic?
Both directions and the upcoming stricter requirements for containment show impressively that future solutions in the pharmaceutical world will have to be considered in a very individually targeted manner. All possibilities and risks must be systematically considered well in advance of a new production. Here it is important to consider whether all disciplines are present and available in a company. Involving external experts will be of great importance for successful projects in the future.
Looking to the future, robots in aseptic production have a great potential to operate aseptic processes without human intervention. This has the advantage of minimising the aforementioned drug safety risks. Another consideration to the use of robots in aseptic production is cost effectiveness. The use of robots requires virtually trouble-free equipment which makes the output more predictable and reliable. Safety stocks can be safely reconsidered at this high level of value creation.
Due to the high investments and changeover times, such plants will probably be reserved for products with large batch sizes, high value and consistent formats for the time being.
The increasing demand for small batch sizes poses a new challenge, and the market offers modular solutions that meet the respective requirements by combining individual modules. In addition to the high requirements for drug safety, the decisive factors are the flexibility of such systems with regard to different formats and the variability to produce vials, carpules and prefilled syringes for the market with short cleaning and changeover times. The cleaning and changeover of such modules can be done separately from the production line and thus significantly increase the line output.