Injectables last year accounted for 49% of the global pharmaceutical clinical pipeline, an increase of 6% since 2015.1 Much of this growth towards injectables relates to the development of highly specialized or personalized drug products that require formulation technologies to deliver small molecules, peptides, proteins, and nucleic acids for new treatment modalities across a wide range of therapy areas. It is common to design such products for systemic delivery, localized delivery to sites such as the eye, joints, brain, organs, tumors and the spine, or the targeting of specific genes, cells or disease sites.
This shift towards specialized or personalized parenterals is reflected in the fact that of the 38 injectable drug products approved by the FDA in 2019, more than a third are supplied in relatively complex powder, suspension or lyophilized forms.1 Such complex products can face significant stability, sterility, and scalability challenges that can affect the final dosage form, the method of sterility assurance, and the nature of equipment utilized during manufacturing and filling.
For example, terminal sterilization methods such as gamma or e-beam irradiation are commonly used for many drug products due to its effectiveness and reliability. However, for many complex parenterals, terminal sterilization can result in product degradation and loss of effectiveness. These conflicts can necessitate the implementation of specialized equipment solutions for the aseptic manufacturing and filling of such drug products.
Furthermore, the ability to accurately deliver an API to the required site of action within the body has also facilitated a shift towards low-dosage medicines where biological activity can be exhibited at extremely low concentrations. These highly potent APIs (HPAPIs) are commonly being developed for oncology or immuno-oncology treatments, as well as hormonal imbalances, chronic pain, glaucoma and rare diseases. It is a key regulatory requirement during every stage in the handling of HPAPIs that robust processes are utilized to maximize occupational health and safety and minimize the risk of cross contamination with other products. Once again, specialized equipment can be required to facilitate the manufacturing and filling of such drug products with HPAPIs.
Finally, our increased understanding of biology and genetics now allows scientists to develop highly individualized or personalized drug products that can be precisely tuned to optimize safety and efficacy within well-defined patient populations or even individual patients. Such products are not only complex in design but require much smaller batch sizes. Traditional equipment utilized in the manufacturing and filling of drug products at commercial scale is primarily suited to the production of tens of millions of doses or more per year. However, the use of such systems with complex or low-volume drug products can be unfeasible due to their inflexible design configuration or cost inefficiencies. Should a pharmaceutical company also seek to fill a drug product in multiple primary containers, such as vials, prefilled syringes or cartridges for use with wearable injectors, the use of additional filling lines or significant delays for the interchanging of parts would be required.
As injectables continue to evolve in formulation and dosage form complexity, and shift towards smaller batch sizes, a growing number of pharmaceutical and biotech companies are seeking access to a new, more versatile generation of equipment that can address the specific requirements of these low-volume/high-mix manufacturing projects.
As a global CDMO for advanced drug delivery with decades of expertise with complex parenterals that require polymeric or liposomal technologies, Evonik has established advanced manufacturing capabilities in areas such as continuous microencapsulation, precise hot melt extrusion, liposomal extrusion and microfluidics. It has also sought to collaborate with industry partners to develop and commercialize a new class of aseptic filling line to address unmet industry needs for the aseptic filling of complex parenteral drug products.
Earlier this year, these efforts culminated in the qualification of a fully automated modular aseptic filling line at its parenteral drug product manufacturing facility in Birmingham, Alabama (Figure 1). The VarioSys® aseptic fill line, which was developed for Evonik by Bausch + Stroebel, is designed to efficiently fill parenteral drug products in powder, liquid, suspension or combination form. It enables the effective manufacturing of multiple drug delivery forms through the efficient interchanging of components or equipment to fit each filling process step or primary container size or shape.
In addition to the filling of powders, suspensions and liquids, integrated lyophilization capabilities can help to optimize stability controls for drug products that require this additional processing step. When using 100% in process control (IPC) check weight, up to 14,000 vials in powder form, and 15,500 vials in liquid, suspension or lyophilized form, can be filled per 8-hour shift to meet the clinical or commercial-scale requirements of complex drug products. This number significantly increases when using statistical control of 5% IPC check weight (Table 1). The modular system also features a small footprint, taking up only 6.5 m2 of isolator space occupied by the filler.
Modular Design Flexibility
The VarioSys® Line features SKAN PSI-L (Pharmaceutical Safety Isolator L-Flange) and SARA (Safe and Rapid Airlock) isolator technology that allows it to be adapted to the specifications of each product configuration. Each isolator rests on movable trolleys to support the efficient interchanging of individualized equipment to match each process step. The process to interchange trolleys can be completed within approximately 30 minutes. As such, the line can be easily adapted for different products and container types such as ready-to-fill syringes, thereby limiting equipment downtime. Filling equipment can also be completely removed from the clean room for cleaning or maintenance, while the line continues to run with another trolley module.
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API and Dosage Form Versatility
The system can aseptically handle a broad variety of dosage forms including powders, liquids or suspensions, liquid-suspension combinations, and lyophilized powders for solutions or suspensions. Both powder and liquid filling can occur in the same Grade A isolator modular chamber. Multiple API vessels and containers can be used during a single batch and can be switched out without having to pause filling activities. An integrated peristaltic pump can also precisely feed even highly viscous liquids up to 35 cP within a filling range anywhere between 0.1 to 100.0 mL.
Accuracy and Efficiency
The combination of volumetric and gravimetric fillers enables consistent product control and precise dosing down to ±0.2% for many formulations (Figure 2). The risk of product loss can be minimized as the system automatically adjusts during operation to optimize filling precision. A top-off feature eliminates the risk of under-filled vials or primary containers, while a weight check feature allows up to 100% weight check verification to maximize quality control. The potential for product loss occurring within transfer tubing is also minimized due to its compact design that allows product tanks or vessels to be placed close to the machine. An optional nitrogen overlay may also take place in the filling isolator chamber to allow handling of oxygen-reactive or humidity-sensitive products.
Optimizing Product Stability and Shelf Life
Lyophilization is commonly used to improve the stability and extend the shelf life of complex parenterals. However, the process of freezing and subliming liquid, leaving a dry powder behind, requires precise control and containment to preserve product sterility. The VarioSys® operated by Evonik features a GEA LYOVAC™ Lyophilizer with ALUS™ (Automated Loading and Unloading System) technology. ALUS™ seamlessly loads vials into the lyophilization chamber as they come off the filler, with minimal operator intervention. These vials are then unloaded automatically after the freeze dry cycle. For products which do not require a lyophilization step, vials can bypass this segment and instead directly enter the capper/crimper system in the next module.
Maintaining Sterility
SKAN isolators are used to create a fully integrated, sterile environment throughout the entire filling process. Integrated active air samplers are installed in each chamber, with two in the critical zone of the filling chamber. These will automatically stop all filling operations if acceptable levels of operation are exceeded. The SARA airlock can also be completely sealed off from other isolator chambers, enabling components to be added to the fill line in a sterile manner without breaching the main chambers. This flexibility allows the system to be utilized for the production of larger batches over an extended duration. Once components are introduced into the SARA, a single VHP cycle can be performed, after which the SARA can be opened to the other isolator chambers and materials can be passed through. Such flexibility enables a level of aseptic manufacturing that is not easily achieved in traditional fill lines.
A depyrogenation tunnel continuously supplies sterile vials or containers throughout the entire filling system in a manner that minimizes the need for operator intervention. Each container can be fed, washed, and depyrogenated in an inline sterile process with a residence time of approximately two hours. The depyrogenation tunnel can also be paused during filling activities, to enable maximum efficiency outside of 24-hour operating conditions or for multi-day batches.
To further ensure sterility to product specifications, the capper/crimper automatically performs full system checks from the insertion of the stopper through to the final crimping of the seal. When the vials enter the crimper, a further check is also performed to verify the stopper is properly seated so the seal is placed correctly. The integrity of each vial is also checked by several sensors before it advances onto the final external vial washing station. Any vial rejects are automatically segregated for removal, inspection and disposal.
Compatibility with Highly Potent APIs
The system is equipped with a PennTech external vial washer postcapping system that can ensure operator and customer safety when handling high potent APIs. The negative pressure enclosure rinses vials with WFI (Water-for-Injection) while also providing the option of adding a detergent to clean potential contaminants from the outside of the vials. Following washing, vials or other primary containers go through a blow-dry station prior to their automatic transition to the offloading table. The whole process is completed in a controlled and contained system, enabling the line to operate in a fully integrated manner without delay during the handling of highly potent products.
Conclusion
Evonik has recognized unmet and emerging market needs for complex and personalized parenteral drug products with its implementation of the VarioSys® aseptic filling system. The line enables cost effective manufacturing of multiple drug delivery forms through the efficient interchanging of components or equipment to fit each filling process step for powder, liquid or suspension combinations. As a result, it is ideal for low-to-mid volume, high-mix manufacturing projects. This new capability further complements the broad portfolio of functional excipients, drug delivery technologies and CDMO services that are available to pharmaceutical companies seeking to develop drug products for the delivery of small molecules, peptides, proteins, and nucleic acids.
References
- PharmaCircle. 2019 Global Drug Delivery & Formulation Report
Author Biographies
Dr. Maaike Everts is the head of strategic marketing for parenteral drug delivery at Evonik. [email protected]
Jerod Price is the head of drug delivery operations for parenteral drug products at Evonik. [email protected]