Manufacturers of parenteral drug products face numerous challenges to fulfilling their business needs. Often, the business needs themselves are difficult to define for the long term. The trend of fewer high volume products and more low volume, niche products requires a well-planned operational strategy. The need to manufacture more specialized products with a diversity of drug delivery formats poses challenges in designing new or renovated manufacturing facilities for companies that must control capital spending, while still aiming for a design that will function for years to come. Fortunately, facility and process technologies are keeping pace with industry needs perhaps better than ever before. These include increased automation, barrier technology, single-use and ready to use components, and flexible format filling lines. Yet, the availability of solutions does not automatically yield an efficient and compliant facility. A disciplined, holistic approach to design and selection of technology increases the chance of success in meeting immediate and long term business needs. Here we explore critical elements to design and how they integrate today’s state-of-the-art technologies.
Definition of Business Drivers
When starting a new facility design or even renovating an existing one, it is important to begin with the end in mind. Clear objectives and an understanding of how the facility will be qualified and operate must be established before any design work commences. Projects always start with a business driver. The business case for a facility can vary to include capacity increases, new product capabilities, or even compliance upgrades to maintain production. In addition, the business case should determine whether the facility is meant to support large-scale commercial production or small-scale/pilot manufacturing as equipment and facility solutions can be very different depending on the production scale. Often the full business plan is not known and designers are presented with the challenge to not only design for the current product portfolio, but to also create a facility which has the flexibility for future products that may or may not be known.
Large-Scale Facilities
Large-scale commercial facilities are designed to produce large quantities of products and to run continuously over long production campaigns. Often, the profit margins are low and suppliers rely on high speed filling lines to produce as many pieces as possible as quickly as possible. The emphasis is on the filling line with the goal of maximizing its utilization. The filling line often represents the single greatest investment in a project and budgets don’t usually allow for a “back-up.” As a result, design teams understand that when the filler is not running, the company is not making money. Their job is to develop a facility design which optimizes the use of the filler and to keeps it running. To support large production quantities, robust engineering solutions should be employed. Novel solutions will likely take longer to qualify and may be more difficult to run efficiently.
The greatest threat to aseptic production is contamination. The largest source of contamination is people. Choosing isolator technology eliminates personnel from the aseptic environment and greatly reduces the risk of product contamination. Isolators are not new, but the technology continues to improve year after year with advances in vaporized hydrogen peroxide (VHP) bio-decontamination systems and component transfer equipment. In addition, many suppliers provide ready-to-use (RTU) components (stoppers, plungers & caps) that are prewashed and pre-sterilized in containers with rapid transfer ports (RTP) that are easily docked to the isolator for immediate use. Isolators also vastly decrease the complexity of the cleanroom environment. With the aseptic conditions being met within the equipment, operators can enjoy a more comfortable environment which is not only easier to maintain, but more economical to operate (a direct result from reduced air changes and gowning requirements). Automation should be utilized in large-scale facilities as much as possible to minimize reliance on procedures and establish production steps that are reproducible and easily validated. Some examples include automated parts washers and component prep systems which can replace manual production steps. Automation can also include continuous processing. Automated vial washers and depyrogenation tunnels can be fed continuously to maintain filling operations. On the other hand, batch processing of these components is limited by equipment size and requires additional operator handling steps, thereby increasing production times and the attendant risk of contamination. After filling, continuous processing techniques should be used to transfer partially stoppered vials to lyophilizers, where they can be loaded automatically with isolated loading systems. These systems can also unload the lyos and transfer the vials to the capper for final crimping. Interventions occur through glove ports and the operators are never exposed to the aseptic environment. Manual loading and unloading of lyos, however, require many handling steps by operators who must be in the aseptic environment. These operators pose a constant risk of contamination and the success of the run often depends on their aseptic technique. Automation can also be extended to the cleaning or decontamination of equipment and the aseptic environments within them. Isolators use vaporized hydrogen peroxide systems (VHP) for sanitization. These automated systems have cycle times that can be as quick as two hours and greatly improve the time it takes to “turn over” a production suite between products or at required cleaning intervals.
Single-use disposable systems (SUDS) can also help reduce equipment turnover times. Today’s filling lines can accommodate SUD product fluid paths and filling needles, allowing these hard to clean components to simply be discarded. They arrive pre-sterilized in bags with rapid transfer ports that can easily be docked to the filling isolator. Implementation of SUDS technology allows manufacturers to focus less on support functions and more on producing their own products.
The architectural design of large-scale facilities can be as important to production as the process equipment. Creating an optimal layout and choosing the right finishes can affect how efficiently the facility operates and how well it holds up the demands of daily operation and cleaning regiments. The layout of the facility must directly support the production steps. As mentioned above, the goal is to keep the filling line running as much as possible. Materials flows should be studied to provide adequate space for staging for both formulation and filling activities so that the filling line is never waiting for product or components. Adequate staging and its location post filling can be just as important so the line can be cleared quickly preparations can be started for the next run.
Aseptic facilities are designed to minimize contamination of sterile products. Choosing the right clean room system can directly affect the achievement of this goal. Clean room vendors typically offer complete systems with facility components that are designed to work together. They also have many pre-engineered details to facilitate equipment installation and integration. This approach has many advantages over “Stick built” systems where components are field integrated. Clean rooms are required to maintain pressure cascades between production areas and transition zones. Maintaining pressure is critical as these parameters are validated and monitored. The best clean room systems offer PVC coated wall and ceiling panels which are chemically welded together ensuring a tight seal. Stick built construction and lesser clean rooms systems rely on silicon sealant at these joints which can degrade over time and requires constant maintenance. Other benefits of clean room systems include quick and clean construction and integral walkable ceilings which provide maintenance accessibility to interstitial spaces above the ceiling.
Small-Scale/Pilot Facilities
Small or pilot-scale facilities can be quite different in their design and the equipment they employ. They tend to produce smaller quantities of higher value products in multiple container types and sizes. These facilities require innovation and flexibility, but they still need to adhere to the same regulatory requirements as the larger commercial facilities. Although the goal of the small facility is still to formulate and fill product, the batch sizes are much smaller and the facility “turn-around” time between products tends to be the bottle neck.
Filling line vendors have responded to the need for more flexibility. Many now offer multi-format machines which can fill a range of containers sizes and types including vials, syringes and cartridges. These fillers are also available with isolators to improve turn-around times and reduce risk of contamination as mentioned above. Some suppliers now even offer smaller, more affordable isolators with a plug and play baseplates allowing filling systems to be switched out depending on the process needs and production steps. These isolators are modular and can be combined in arrays to support a variety of production methods. Other suppliers offer flexibility by integrating handling of both syringes and vials in the same machine, sometimes utilizing robotics. Isolated filling lines can also take advantage of rapid VHP chambers which can be used to sanitize and transfer components into the isolator at any time. Recent developments have led to validated sanitization cycles as quick as twenty minutes.
In addition to isolator technology, SUDS can greatly improve the efficiency of a small volume facility. Disposable formulation systems eliminate the need for vessel cleaning and lend themselves to the smaller formulation batch sizes of pilot facilities. Of course, the small-scale filling equipment can also take advance of the disposable fluid paths and filling needles to speed up turnover times. Disposable aseptic connectors provide additional flexibility as they are easy to use and don’t require the cleaning and sterilization of traditional aseptic connections.
The architectural design of small volume facilities can also play a key role in their functionality. When isolators are utilized the facility can take advantage of the “ballroom” approach where the filler is central in the layout within a large open room and all other support functions surround it. This provides the required filling flexibility along with adequate separation of critical production steps. Conventional aseptic facility designs require separation of aseptic operations from non-critical production steps. Such facilities are less efficient because of the procedures and production steps required for entering an aseptic environment. They tend to be less flexibly and harder to adapt to changing processes.
Pre-engineered clean rooms systems can also be utilized in these smaller facilities as the benefits mentioned above still apply. A risk assessment can be done to determine which approach is best depending on the facility location, availability of skilled labor, project schedule and budget.
Conclusion
Designing aseptic facilities to meet today’s product demands and regulatory requirements can be quite a challenge. Fortunately, advancements in technology and knowledge of operational requirements continue to lead to the development of equipment and components which respond to these needs. The technology alone, however, cannot guarantee an efficient and productive facility. It is important to first understand the business and operational goals of the facility. Only then can a fully integrated facility be developed which meets these goals and fulfills the business objectives.
