The global market for biopharmaceuticals continues to grow at a rapid pace, with a 9.5 percent compound annual growth rate (CAGR) predicted over the next eight years. This translates into more than $500 billion in projected growth; thus, it is no surprise that biopharma manufacturers around the world are investing heavily in new facilities, technologies, and pipelines for the manufacturing of biologic products.
Even so, the need to prevent contamination places stringent handling and packaging requirements on biopharma manufacturers. The sterilization of equipment often requires steam autoclaves as well as dry heat, and may even include treatment by irradiation. In fact, the U.S. Food and Drug Administration (FDA) mandates that all containers used in a sterile manufacturing process must be sterilized prior to contact with the drug product itself; and the agency has recently recalled a number of pharmaceutical products for failing to comply with this requirement.
For this reason, a growing number of biologic manufacturers are turning to new aseptic fill-finish technologies, including blow-fill-seal systems and single-use equipment. Even as these new technologies see increasing adoption, the core demands of fill-finish processes remain the same: to keep equipment and formulations free from contamination and to package the product in a way that preserves the biochemical conditions most conducive to the safety and efficacy of each biopharmaceutical product.
Part 1: Facility design, sterilization system selection, and packaging pipeline design.
The manufacturing facility itself must be designed to safeguard aseptic conditions.
When designing a fill-finish manufacturing process, the first consideration is the design of the facility in which the operation will be performed. An aseptic fill-finish system requires a cleanroom; and the maintenance of this aseptic environment requires far more than simply sterilizing equipment.
The cleanroom’s air, for example, must be circulated through a high-efficiency particulate air (HEPA) filtration system, and this airflow must be monitored for the presence of even minor amounts of contaminants, which can jeopardize the sterility of the entire manufacturing pipeline.
The layout of the cleanroom, too, must funnel workers and equipment from the areas with the highest sterility toward areas with the least. This type of layout prevents inadvertent contact between non-sterile tools and those that have been pre-sterilized. In addition, the room’s layout must enable disposable components, such as stopper bowls and needles, to be easily replaced without disrupting the overall flow from sterile to less-sterile areas.
In a cleanroom, any equipment or packaging materials using aluminum seals must be prevented from coming into contact with any equipment that may become contaminated by contact with aluminum. Stoppering equipment, in particular, must be kept separate from aluminum and other potential contaminants, and should be placed as near to the lyophilizer as is feasible, to keep the time from lyophilization to stoppering as brief as possible.
Techniques used to sterilize fill-finish systems must be appropriate for the formulation and equipment used.
Before equipment or packaging can enter a cleanroom, it must be sterilized. The systems used to sterilize equipment must be chosen carefully, as each approach will have a different impact on various formulations and packaging materials, as well as on various types of contaminants that may be present on equipment and tools used in the fill-finish process.
The most conventional sterilization technique is steam autoclaving, which effectively eliminates many pathogens. However, this technique may degrade delicate components of the formulation, such as amino acids, which are essential to biologic drugs. It may also prove detrimental to tools and packaging that are highly sensitive to heat and moisture. Still, this technique remains a trusted standby for sterilizing fill-finish equipment.
An alternative to steam autoclaving is the use of dry-heat ovens, which can sterilize equipment in batches, or via a tunnel that circulates extremely hot, dry air over bottles and other equipment. While this technique avoids exposing fill-finish equipment to moisture, it can still cause damage to heat-sensitive formulations, or to equipment made of materials that degrade under very high temperatures.
A growing number of pharma manufacturers are now adopting radiation sterilization technology as a supplement to traditional techniques like steam autoclaving. Ionizing radiation has been shown to kill many types of bacteria that survive heat sterilization, while gamma radiation achieves an even higher penetration and termination rate. When utilizing radiation to sterilize fill-finish equipment, however, a manufacturer must consider the impact of irradiated particles on the components of the formulation.
Manufacturing processes such as lyophilization must be performed aseptically.
Many biologics must be lyophilized prior to bottling. A sterile fill-finish step adds additional constraints to the already numerous risks and challenges of lyophilization, requiring the design of a packaging pipeline that minimizes the transfer time between the lyophilizer and the vial or bottle.
Many manufacturers address this challenge with automated or semi-automated loading procedures, in which a sterilized core is transferred directly into each vial without leaving the lyophilizer. This type of filling process requires an extraordinarily precise setup: the vials must be prepared in batches, with their stoppers resting on their edges. The vials are then carefully loaded into the lyophilizer, where they undergo the freezing stage along with the drug formulation.
After the primary and secondary drying steps have been completed, the fully lyophilized drug is automatically inserted into the vials, and the shelves within the lyophilizer are lowered, causing the stoppers to become attached to the vials, thus completing the aseptic fill-finish process without ever removing the drug product from the lyophilization environment.
In Part 2 of this two-part series, we will discuss why manufacturers must adopt new fill-finish technologies while also carefully considering the cost-benefit tradeoffs of doing so.