Key points
Introduction
Recent years have seen significant improvements and innovations in technologies used in aseptic processing. With the rise in demand for small batch, novel therapies, manufacturers are looking to develop more vigorous and flexible containment strategies using new and innovative solutions.
The regulatory requirements around sterile manufacturing are becoming more stringent, with increased emphasis on using the best available technologies and performing comprehensive, science-based risk evaluations of procedures.
The industry is seeing significant developments in technology in response to the hazards involved in aseptic processes, as product sterility must be ensured and contamination prevented to avoid potential consequences to patient safety.
Current market landscape
Containment technology experts are continuing to innovate to meet the evolving requirements of the sterile product manufacturing sector. This is one of the factors driving growth in the global advanced aseptic processing equipment market, which is set to reach a CAGR of 3.8% between 2017 and 2024 [1].
Current regulations for aseptic processing are rigorous, especially in the case of guidelines around cleanroom areas for the manufacture of sterile products, which must be classified according to the necessary characteristics of the environment. These environments must meet strict classifications in accordance with ISO14644 in order to be categorised as grade A, B, C or D.
More personalised therapies that are targeted to meet specific requirements, such as those of a small group of patients, are becoming increasingly popular, generating the need for an increased amount of small batch manufacturing.
Equipment for the production of sterile goods must be cleaned, decontaminated and sterilised between batches to prevent contamination of the following batch. If this is not handled correctly, a manufacturer’s start up and shut down process can be significantly delayed.
This is a particular challenge for the growing number of contract development and manufacturing organisations (CDMOs) that must be agile enough to handle multiple products for multiple clients within their facilities.
Existing cleanroom technologies
Sterile manufacturing environments are open to many sources of potential contamination, and thus potential hazards during the manufacture of sterile products, if they are not managed correctly. Patient safety could ultimately be put at risk should microorganisms, particles or endotoxins enter the manufacturing environment.
One of the main sources of contaminants in the cleanroom environment is the operator as the average human carries a multitude of microbes and bacteria.
Other potential sources of contamination include the equipment and raw materials used as well as the environment itself. Multiple technologies have been developed in response to the need to ensure the safe and sterile transfer of APIs and formulation ingredients during aseptic processing.
One such development is isolator technology: isolators provide an airtight barrier around the aseptic processing line and can be employed in cleanroom environments to minimise the risk from contaminants.
Current isolator design incorporates unidirectional airflow into the enclosure’s chambers and can provide a specialised environment tailored to the needs of the product; humidity, oxygen, temperature and pressure levels can all be adapted.
Restricted access barrier systems (RABS) are also often used in sterile manufacturing environments. Several elements must be in place in order for a RABS to be fully functional, including properly designed equipment, management oversight, a quality system and proper surrounding room design to maintain ISO 5. [2]
Recent years have seen RABS technology become more widely used, as it provides a barrier between workers and processing lines while offering operators the opportunity to interact with products as necessary.
High-efficiency particulate air (HEPA) filtered airflow is also incorporated in RABS technology, significantly reducing the “probability of a non-sterile unit” (PNSU). RABS can be opened to allow process intervention and has also been found to yield similar PNSU data to isolator technology, which must remain closed during operation.
Challenges associated with current technologies
Despite their benefits, both isolators and RABS have disadvantages. Manufacturers using isolator technology may face difficulties when transferring materials in and out of the chamber.
A docking isolator may need to be used and the interior may need to be sterilised before materials are transferred, delaying the shut down and start up process between batches. Isolators also have slower start-up times in comparison to RABS, meaning product changeovers are often less efficient.
In comparison to isolators, the closed solution provided by RABS technology is less robust, providing lower integrity chambers. Where isolators can be decontaminated through an automated process, which allows for a high level of biocontamination, RABS rely on manual cleaning processes.
All product or process contact parts within a RABS must be sterilised or steamed-in-place (SIP) prior to use, which creates a more complicated cleaning process than in a traditional sterile area.
As the demand for aseptic processing continues to grow, the disadvantages associated with both technologies pose considerable challenges for the industry. New technologies are now being investigated by pharmaceutical manufacturers as they look for ways to improve efficiencies, lower costs and reduce the risk of contamination.
Many of these technologies work alongside isolators and RABS set-ups, which can allow firms to integrate them into their aseptic processing lines. This can generate significant cost savings for firms that may otherwise have had to overhaul their processes entirely.
The advent of new technologies
In response to these challenges, the industry is starting to implement single use technologies and systems. The boost in efficiency and ease of use that disposable parts can provide has led to these technologies being adopted by the industry.
Split Butterfly Valve (SBV) technology, for example, has been developed further to create a single use solution for contained materials transfer using a single use passive, a disposable version of the passive mating half of the SBV, and ChargeBag single use packaging.
SBVs are made up of an active half and passive half and enable the transfer of a product from one container, process vessel, isolator or RABS to another without compromising sterility.
As well as being used as part of an isolator or RABS set-up, the technology also provides an alternative to traditional barrier techniques and is often considered a more practical option to achieving guaranteed product sterility. The technology can also offer improved ergonomics and reduce reliance on cleanroom environments.
When used, the active half of the SBV is attached to the receiving vessel, while the passive half is attached to the flexible bag or discharging drug container.
When the two halves of the disc are brought together a single plate is created, which allows product to flow on the interior surface of each half. This means that when the two halves are detached, the external faces remain clean and can be exposed to the process environment safely.
When the valve of the SBV is sealed, an opening is created between the discs, which means decontaminating gas can be flushed through and decontamination can take place in a closed environment.
Validation occurs using chemical indicators, which confirm full coverage of the enclosure has been attained. This is followed by biological indicators, to ensure a 99.9999% reduction (or 6-log reduction) in bacterial spores has been achieved.
The disposable passive half of the valve, known as a Single Use Passive (SUP) now exists with SBVs. Once docked with the active unit the SUP can be opened, ensuring new single use products are compatible with existing SBV systems in the field.
The need for cleaning and sterilising the passive half of the system is eliminated through the use of these disposable products, which allows for increased productivity.
Due to the importance of ensuring sterility during product manufacturing, there is also growing use of new smart technologies. Wireless monitoring solutions such as the VERIFI SMART monitoring technology can provide firms with vital equipment performance data when installed onto an SBV.
Maintenance teams, as well as compliance and health and safety teams, can make informed decisions on the management of their maintenance programmes armed with the necessary information provided by monitoring technology.
In addition, multiple manufacturing locations are also now being used by pharmaceutical companies. Much of the development, manufacturing and packaging of products is entirely outsourced, and shipping between countries is often involved as more drug products are moved between facilities.
Technologies that ensure the integrity of sensitive products while in transit are now being investigated by manufacturers, as current solutions often pose significant challenges. For example, the use of solutions like fibre or plastic drums with flexible liners can pose challenges around the filling, sealing, handling and emptying of packages.
Final thought
Current technologies such as isolators and RABS offer substantial benefits to manufacturers, but advances in the industry have seen manufacturers looking to develop their containment strategies to remain competitive and ensure compliance.
The industry has seen an influx of innovative new technologies, such as single use technologies, smart monitoring and multi-location solutions, in response to the specific manufacturing and handling requirements of sterile products.
As regulations continue to tighten and the need for flexible manufacturing facilities becomes more prominent, the industry will no doubt continue to innovate and use technology to improve their manufacturing processes, so they are fit for purpose now and in the future.
