A growing number of inventive drug developers are turning away from large-batch, mass-market developments toward the important and lucrative segment of small-batch, personalized medication and orphan drugs. Simultaneously, regulators continue to increase the complexity of regulation, especially in data recording, traceability and cGMP. As a result of these two phenomena, drug development and production costs climb. Competitive developers and manufacturers must create a wider variety of formulations at an efficient rate while constantly meeting the high standards enforced by regulators. Their tools, including fill-finish system machines, must accommodate these goals by providing exceptional flexibility and repeatability while adhering to increasing complex regulation.
Fill-Finish Flexibility for Small-Batch Applications
Tighter regulation demands fewer interventions and increased environmental monitoring and in-process-control (IPC) in drug production. Barrier separation systems answer these pressures, encasing the filling system inside an isolator or restricted access barrier. These ensure process sterility by housing all fill-finish functions within one unit. Nevertheless, these machines require a high degree of flexibility. A completely sterile but difficult-to-customize machine would encumber most producers and research teams. The trend in the market strays from large-scale fillers toward more small-batch, personalized machines that support quick changeover.
The primary point of customization for most fill-finish systems is format parts. Commonly nylon, these custom-designed elements perfectly match the specific task at hand, machined to fit a particular size of vial, cap, stopper or other part. Format parts offer the required functionality for drug production trends — the ability to handle a variety of containers and caps — but bear a cost as well. The more format parts a system requires, the slower the changeover process.
Self-adjusting system machines cut down on the number of format parts requiring exchange. New technology allows a machine to automatically adjust all settings and parameters on the machine that are necessary to meet the differences in vial sizes, fill volumes, and more. One such machine, the Watson-Marlow Fluid Technology Group (WWMTFG) Flexicon FPC60, features a dramatically reduced count of format parts. As the only manufacturer to accommodate all cap and stopper sizes and types with a single bowel design, for instance, WMFTG allows users to avoid unnecessary changeover delays; for other machines, these bowels are format parts. In fact, since altering vial neck size and diameter usually correlates to a very significant change in the volume of the vial, for the majority of customers who rarely change cap and stopper sizes, the Flexicon FPC60’s format parts rarely require changing. This economy of components to change enables expedited changeover for greater effective flexibility from one batch to the next.
Once a small-batch production manufacturer, CDMO/CMO or research and development operation has optimized its machinery for quick setup, the remaining factor of changeover speed is cleanability. Indeed, self-adjusting units offer an advantage with regard to cleaning, too. The Flexicon FPC60 favors a sleek design, with attention given to eliminate inaccessible areas, and single-use capabilities for easy cleaning compared to machines with more interchangeable parts..
Fill-finish Repeatability for Small-Batch Applications
The same functionality that optimizes flexibility can enable a greater benefit for researchers and drug manufacturers. For systems that require manual setups, various operators are tasked with performing the setup procedures. This invites slight — or major — inconsistencies and inexactitudes to creep into machine setup and affect the product. Consistency between batches is a major challenge.
Repeatability is critical to commercial success in the marketplace, but, moreover, it is a regulatory prerequisite. Regulators regularly demand access to extensive, complete records of development and production. In short, any system must not only do processes, but also track all processes in real time to achieve the level of traceability that regulators require.
Automation addresses the challenge of repeatability in a number of important ways. First, limiting the amount of operator-impacted setup allows operations to achieve consistency across all operators and across all batches at all times. The Flexicon FPC60 allows users to set up recipes with all the tolerances for vial diameter, vial height and other parameters preset and easily accessible in a program. Once a recipe is set up, operators simply recall the recipe, and the machine automatically adjusts all settings and begins. The recipe is digitally fool-proofed against misremembering, and the automated self-adjusting system removes human error from the actual mechanics of the setup process.
After the fact, the Flexicon FPC60 can recall all batch data and see all audit trails — exactly what functions have been keyed into the machine at what time by which operators. This illustrates the second major benefit an automated, self-adjusting unit provides. As regulation increases, the demand for excellent documentation of all components and functionality of the machine is vital.
Automated systems can generate highly complex audit trails that accommodate an increased level of oversight, all without adding labor costs or leaving room for human error. Furthermore, the Flexicon FPC60 allows remote data access and recipe setup from outside of the cleanroom. This detailed, saved electronic data also serves as an asset to research and development professionals, who can easily compare the characteristics of different recipes and run complex analytics on the batch and production data. Relatedly, these systems enable excellent quality assurance: the Flexicon FPC60, among other IPC systems, can actually measure and independently validate the force used to secure a cap on a vial.
Other Small-Batch Fill-finish Challenges: The Biologics Example
One of the more promising areas of drug development and small-batch production: biologics require very specific conditions. Some pumping processes, such as a piston pumping, can exert forces on cells that can rupture the biologic matter. This material loss can create a major drain on resources, since this genetically engineered matter can cost upwards of $100,000 per milliliter. This area of drug production, therefore, calls for the peristaltic pumping offered by some fill-finish system machines. Peristaltic pumping action is a low-sheer, gentle massaging process that does not destroy or damage cells. With a peristaltic system such as the Flexicon FPC60, cells remain fully intact through the process. Moreover, other systems can waste 5–10 mL of product during pump priming and calibration. The Flexicon FPC60 features an option for no waste in the batch startup, so a producer with $100,000/mL biologic matter can save between $500,000 and $1,000,000 per batch.
The delicacy of biologics underscores the importance of an uncontaminated process. Previously, drug producers used rapid decontamination chambers in the first stages of preparing vials, whether vials producers washed and prepared them onsite or ready-to-use pre-sterilized vials before they were removed from their packaging. However, this process centered on the application of vaporized hydrogen peroxide, which the ready-to-use packaging was not able to fully resist and would persist as a residue on vials. When cells came in contact with the chemical, the living matter would die. The Flexicon FPC60 instead offers no-touch transfer, a validated process, which debags pre-sterilized ready-to-use vials while ensuring sterile integrity throughout.
Enhance Small-Batch Flexibility and Repeatability with Advanced Fill-finish Systems
In the modern drug market, flexibility and repeatability are critical assets to small-batch developers, CDMOs/CMOs, and producers alike. Fill-finish systems designed to provide flexibility and repeatability offer greater efficiency, capability and traceability for small-batch applications. As competition and regulation continues to pressure businesses in this space, advanced solutions, such as the uniquely configurable Flexicon FPC60 peristaltic fill-finish system can deliver a competitive edge, with leading technology from Watson-Marlow Fluid Technology Group.
