New pharmaceutical products are complex, high-value and hard to manufacture. Drug discovery platforms are creating more clinical drug candidates. These new therapies are targeted at smaller patient populations. As patents for top selling biological medicines lapse, the market for generic biosimilars is rapidly growing. Many of these drugs are injectables that need to be aseptically produced in different vial, syringe and cartridge containers.
All of these conditions call for increased flexibility. With India as a centre for generic and biosimilar drug production, its pharmaceutical industry stands to accelerate its growth by adopting advances in standardisation and flexibility. Adopting new technologies will help to bring drug products to market faster and grow market share and profitability.
Conversely, conventional aseptic filling solutions are better suited to large-scale batch manufacturing. Conventional, custom-built solutions hurt manufacturers’ competitiveness because they are expensive, inflexible, and time-consuming to build and validate. In operation, their complex electromechanical components make it hard to decontaminate quickly and typically have changeover processes that can last several hours, up to multiple days.
Indian pharmaceutical companies have taken a strong interest in adopting new production technologies to achieve flexibility. The following section describes how robots are integrated within a gloveless isolator for the production of sterile injectables. Rather than simply integrating robots into conventional designs, this approach redesigns the aseptic filling process, providing a flexible system that can meet both current and future demands.
The Aseptic Filling Workcell approach
The Aseptic Filling Workcell is a gloveless isolator in which specialised robots fill liquid drug products into nests of vials, syringes or cartridges, then close (stopper or cap) the containers. The idea of the workcell comes from the semiconductor industry, where significant productivity and quality gains have been made through the use of standard robotic workcells.
The Aseptic Filling Workcell is a standard product with the built-in flexibility to fill and close multiple container types. As such, it can be built quickly and represents a scalable platform on which manufacturers can ramp up their operations to meet demand. With low downtime between batches, it can be effective at both clinical and commercial quantities. This helps speed to market by enabling manufacturing process development earlier in a product’s lifecycle. By integrating filling and handling robotics within a gloveless isolator, there is far lower risk to the product through particulate generation or human intervention.
Flexibility in operation
The critical benefit of the Aseptic Filling Workcell is its operational flexibility in both operation and facility design. Using the Workcell approach on a large scale is comparable to a cinema showing multiple movies. For popular movies, the multiplex cinema shows the same movie in more than one small theatre. Similarly, if there is strong demand for a drug, multiple standalone machines can be used for its production. The flexibility and programmability of the Workcell enables a company to be ready for new products in the pipeline, or those brought in by an acquisition.
Standardisation supports manufacturing many different drug products on the same machine, and adapting to changing market forces. Product changeover and decontamination can be achieved in one hour when shifting between container types. By using pre-sterilised, ready-to-use nested containers and closures, the Workcell needs a minimum of change parts to switch between containers. Containers are handled, filled and closed entirely within their nest. For products using the same containers, the batch cycling time is around 30 minutes. Further, a standard Workcell reduces the time and expense needed to add capacity for new products.
Creating a gloveless design serves the purpose of maintaining a higher level of aseptic assurance. The risk to a patient injected with a drug is significant if sterile conditions are not maintained. Robotic handling, a closed isolator and new container / closure methods mean that the Workcell does not have conveyors, mouse holes, vibratory bowls or other sources of possible biological contamination and/or particle generation. Vision systems and automated environmental monitoring support a repeatable, error free process with strong assurance that the product is safe. Human operators, the greatest source of particle generation, are separated from the filling and capping process. All of these new technologies contribute to greater repeatability and product quality.
Taking safety to a higher level
The isolator is called ‘gloveless’ because it does not have glove ports through which operators can intervene in the production process. Conventional systems need glove ports because problems occur that can only be corrected by operators. The role of the operator changes with the Workcell. Only one operator is required, versus several for a conventional system. This operator loads the machines with containers and closures, attaches a fill vessel containing the drug, installs a single-use flow path, and initiates the recipe sequence. When producing cytotoxic drugs like those used in oncology, isolating the operator provides a higher level of safety.
Regulators such as the US Food and Drug Administration have long stated the need for aseptic filling systems to use robotics and reduce human interventions. Indian companies face significant oversight from foreign regulators because much of the country’s production is exported abroad. The Workcell approach improves aseptic conditions for long-term regulatory compliance.
In operation, short changeover and contamination times allow multiple products to be produced on the same machine. A single Workcell is best used with multiple high-value products being filled into different containers. Robotic precision and strong process control through automation create a highly programmable system.
Pharmaceutical process development creates recipes that are strictly followed by the system. Additional product recipes can be added through the human machine interface (HMI). Because production can shift quickly, companies can produce quantities that match with market demand more accurately. Without over or under-production, companies can increase cash flow by carrying less inventory.
For lyophilised (freeze-dried) drug products, the Workcell approach extends to loading and unloading the lyophiliser through an additional lyophiliser loader workcell. ISO 5 / Grade A conditions are maintained as product moves from workcell to workcell. There are no product losses due to fallen vials or glass breakage, since all materials remain within their nest.
Speed in facility design
The root of escalating facility costs and long timelines in the pharmaceutical industry is that every filling line is custom designed and must have the facility designed around it.
Standardising the Aseptic Filling Workcell’s design and simplifying its supporting requirements supports speed to market. The Workcell can be installed in ISO 8 / Grade C space, which costs less to build. As a compact design, it requires a room of only 38 m2 for the machine and space to circulate around it. Infrastructure requirements around air handling and process utilities are also lower, since the actual space inside the isolator is small and closed to the outside environment. Using nested containers and closures eliminates the need for several pieces of supporting equipment. There is no need for an autoclave, washer, or depyrogenation tunnel. This eliminates their capital expense, qualification and validation, and staffing and energy costs.
Pharmaceutical manufacturers can have their facility running a year or more earlier than with conventional isolator or restricted access barrier-based systems. As a standard design, a Workcell can be built, undergo a factory acceptance test and be installed in well under a year.
Reaching the market potential
For India, the Aseptic Filling Workcell approach can enable the market to grow to its fullest potential. The Ministry of Commerce and Industry estimates that the Indian pharmaceutical sector will grow by 15% annually from 2015-2020 compared to 5% growth rate globally. The challenge of growing at this rate is to build facilities that can scale out with demand, and run cost-effectively. The flexibility and scalability of the Aseptic Filling Workcell can support the production of varied product portfolios, including the generic and biosimilar drugs on which India has focused. This new integration of robotics, gloveless isolator and machine vision technologies represents a path for the sector to achieve its full potential in producing sterile injectables for the world market.