A modern take on sterility assurance

Pharmaceutical manufacturers are increasingly looking for strategies to address containment risks. Christian Dunne of ChargePoint Technology sheds light on the benefit of split butterfly valve technology (SBV) in the aseptic processing of sterile active APIs and the final product

Aseptic SBV technology integrated to either the isolator or RABS is a complementary technique that works together to achieve improved sterility assurance

Containment is paramount during aseptic processing. This has led to the development of new transfer methods that are both enclosed and minimise the requirement for operator intervention. Christian Dunne, global product manager of AseptiSafe at ChargePoint Technology, discusses modern containment methods and the advent of split butterfly valve technology (SBV) to offer improved sterility assurance in the aseptic processing of sterile active pharmaceutical ingredients (APIs) and the final product.

Industry outlook

Contract manufacturing in the pharmaceutical industry is expected to reach US$79.24 billion in 2019, rising from $54.54bn in 2013, with substantial revenue expansion predicted for 2025, a market report by Visiongain revealed.

The sterile contract manufacturing sector has experienced steady growth over the past five years with injectables dominating the sector since 2011. The antibiotics market was valued at $39.8 million in 2015, according to a Grand View research, and is expected to see a compound annual growth rate (CAGR) of 4.0% to 2025; a factor that will continue to drive demand for aseptic manufacturing processes.

Another key factor influencing the sterile market is the rise in the cancer segment, which is projected to reach approximately $100bn in value, expanding at a CAGR of 6.5% by the end of 2024. A market report by Persistence suggested that revenue from the cancer segment in the global sterile injectable drugs market could increase 1.7 times by the end of 2024 compared to that in 2016.

As the biopharmaceutical market is constantly expanding, there is an increased need for the development of antibody drug conjugates (ADCs) and an increase in conventional drug manufacturing using high potency APIs.

As reported by Markets and Markets, the global API market is expected to reach $213.97bn by 2021 from $157.95bn in 2016; it is growing at a CAGR of 6.3%. The factors driving market growth include the increasing incidence of chronic diseases, rising prevalence of cancer, technological advancements in API manufacturing, growing importance of generics, rapidly increasing geriatric population and increasing uptake of biopharmaceuticals.

It is vital to both the quality of the final product and the sterility of manufacturing processes to ensure the safe transfer of APIs and formulation ingredients during high potency and aseptic processing. Manufacturers are therefore increasingly looking at more innovative strategies to address these containment risks.

Containment strategies

There are many challenges involved in ensuring product sterility, including investment in containment equipment to protect the product from external contaminants, which could come from the operator or the immediate environment.

As human intervention is present at almost every stage of pharmaceutical manufacturing processes, containment solutions to counter these potential hazards are vital.

Regulations and standards for cleanroom environments have gone some way to alleviating and managing the risks. Ranging from grade A to grade D, there are various approaches associated with each grade, from closed to open handling of a sterile product. In a grade A environment, less than one colony forming unit (CFU) is allowable.

Technological advancements can help to lessen the pitfalls associated with potent compounds and maintaining product sterility. Isolators, restricted access barrier systems (RABS) and split butterfly valves (SBVs) for example, are now in use to safeguard drug products throughout the manufacturing process.

Isolators are an arrangement of physical barriers providing an enclosed working space detached from the surrounding environment. This enables manipulation within the space from outside the enclosure without compromising product integrity. However, isolators can create difficulties in transferring materials in and out of the enclosure. This can require a docking isolator to be connected and its interior sanitised before materials can be transferred. The qualification of vaporised hydrogen peroxide (VHP) systems in isolators can also be difficult, and as a result, there is a need to suspend everything within the cabinet to remove any hidden surfaces.

The RABS approach, on the other hand, puts a physical barrier between operators and production areas, while still offering the flexibility to interact with the process outside a sealed cabinet. To allow a more limited barrier to be permissible, RABS must be set up in high classification cleanrooms, generally ISO 7. This approach enables operators to maintain a distance while allowing the enclosure to be opened if human intervention is required.

In comparison with isolators, RABS can ensure faster start-up times and improve the ease of product changeover. They can also bring improved operational flexibility and reduced validation expenditure. Isolators offer higher integrity chambers for a more robust closed solution.

Aseptic transfer valves have been crucial in achieving high-performance containment

Sterility assurance

New design technologies, such as aseptic SBVs, have been crucial in achieving high-performance containment. Many manufacturers are finding that the use of aseptic SBV technology integrated to either the isolator or RABS for the transfer of material in or out of the enclosure is a complementary technique that works together to achieve improved sterility assurance.

Pharmaceutical manufacturers adopting aseptic SBV technology benefit from a closed handling method that not only achieves the required sterility assurance level and reduces the requirement for manual intervention, but also offers the opportunity to reduce the resource associated with cleaning and validating large areas. The method minimises cleaning requirements and, consequently, downtime while also increasing flow and yield from product transfers.

Use of hydrogen peroxide

Hydrogen peroxide (H2O2) is a versatile chemical. As well as being a propellant to fire rockets, it is a powerful antiseptic, disinfectant, and an immune system booster; the human body even makes use of it to kill viruses, bacteria and dispel toxins.

Hellmuth Walter, the German engineer that pioneered the use of H2O2 in rocket systems in the 1930s, brought his findings to scientists and, nearly a decade after, it is now being used in technology that will help drug manufacturers ensure product quality, and ultimately, patient safety.

The use of H2O2 as a disinfectant is widespread, especially in cutting-edge cleanroom technology.

In the 1980s, after almost a century of using aqueous H2O2 for disinfecting heat-sensitive medical devices and surgical apparatuses, the American Sterilizer Company, (now STERIS) discovered that it has a quicker sporicidal action time when in vapour form in smaller concentrations. VHP has for the past two decades given fast and safe decontamination to areas that may contain bacteria with its application in isolators and cleanrooms.

The H2O2 vapour cycle in SBV devices allows the transfer system to produce a classified area the size of a dinner plate. This enables the downgrading of the external cleanroom environment as it creates an internal grade A environment of its own. This, in turn, delivers process improvements due to the less restrictive operating requirements.

Substantial savings

In terms of cost comparison, the use of SBV can lead to substantial savings. Construction of a grade B cleanroom with grade A manipulations can cost around $860k with annual running costs of $150k. With SBV technology, grade C cleanroom costs are as low as $110k with $3.6k annual running cost.

The gas is applied as small droplets onto a hot plate and vaporised, then blown into an air stream and into a sealed space between the passive and active discs of the valve just before it docks eliminating bacteria in the area.

The biological indicator is then removed and tested to see if any of the spores have survived and could grow. If no spores grow the process has worked and the area is contaminant-free.

Processing time varies between four and 30 minutes, depending on the gassing system utilised. This is extremely fast when compared to conventional airlock or isolator techniques that could be in the region of four to six hours.

Driver of growth

Evolution in the pharmaceutical industry is happening, but production innovation is lagging behind R&D and solutions are required urgently.

Technological advancements within the containment market are helping to support its continued growth, driven by increasing substance potency, regulation and market dynamics such as the growth in biopharmaceuticals.

The key to advanced aseptic processing is the elimination and absolute control of all sources of contaminants, and perhaps most importantly, human exposure. The selection of an appropriate barrier containment technique will be dependent on several factors. Choosing the right containment strategy requires considerable research into what a product needs for effective process design.