Speeding Up Aseptic Processes

Felicity Thomas;

Speeding Up Aseptic Processes

June 13, 2024

By Felicity Thomas

News

Article

BioPharm InternationalBioPharm International, June 2024

Volume 37

Issue 6

Pages: 7-9

Technological advances are aiding manufacturers to streamline aseptic processes and improve time-to-market.

Time as water, a concept. Water with a drip dripping in a glass clock. Creative idea, save the water on a blue background. Global Warming | Image Credit: ©alones - stock.adobe.com

Chronic illnesses or non-communicable diseases that affect the health of the global population are on the rise and, in turn, attributing to a large proportion of deaths and a higher economic burden year-on-year (1). To help combat these long-term illnesses, the bio/pharmaceutical industry has been investing in the development of novel therapies that are increasingly complex in nature.

“The complexity of drugs and their delivery has been increasing over the past few decades,” explains Peter Droc, vice president, head of Drug Product Services, Lonza. “Combined with a growing prevalence of chronic illnesses, this market evolution is putting more pressure on pharmaceutical manufacturers to develop novel therapies that might also have unique formulation needs.”

Many of these novel, complex therapies are biologic-based drugs that are delivered parenterally. “The injectable drug market is experiencing significant growth,” adds Gareth Jenkins, vice president, Science and Technology, Candidate Development, Quotient Sciences. “As a result, robust and efficient sterile manufacturing lines are essential across the manufacturing scales from the early phase to the commercial launch.”

A time-consuming endeavor

“In its very nature, the aseptic processing market is bound to be less efficient than other market sectors,” remarks Nate Smart, process engineer, CRB Group. “[The] focus is delivering critical therapies to vulnerable patient populations in methods that bypass many of the body’s natural defense systems. Therefore, in contrast to other drug product markets (i.e., OSD [oral solid dosage]), the greatest care must be taken to ensure product quality is maintained.”

However, attaining high quality in aseptic processing is a time-consuming endeavor, as manufacturers need to pay close and accurate attention to adherence to strict guidelines, confirms Maximilian Kappler, process engineer, CRB Group. “The highest quality is imperative in aseptic processing to ensure product safety and effectiveness, making it non-negotiable to invest time for quality whether in design, processing, and product testing,” he states.

Regulatory authorities are scrupulous of all aseptic processing facilities and hold manufacturers to stringent standards, agrees Smart. “As a result, aseptic fill lines and their associated barrier systems are custom and costly,” he says. “In many facilities the aseptic filling equipment is the most expensive and longest lead equipment in the facility.”

As a result of these overheads, many manufacturers try to make their lines flexible so that the utility of their equipment can be maximized and new products, formulations, or formats can be added, Smart specifies. “The more products and formats you can run on a single line, the greater utilization and return on investment you can get out of your line,” he says.

“Despite these efforts, fill lines have notoriously low OEE [overall equipment efficiencies],” asserts Smart. “Many lines, even recent installations, have turnaround times of up to 24 hours or beyond. Any reusable critical contact parts (direct and indirect) must be washed and sterilized out of place and then installed in an aseptic manner.”

“The regulatory bodies are currently pushing for a continued reduced risk of contamination,” adds David King, senior director of Aseptic Processing at Samsung Biologics. “This push is focused on the removal of humans from the aseptic filling process, as humans are the primary source (directly and indirectly) of aseptic area microbial intrusions. The primary change is an industry-wide transition from open RABS [restricted access barrier system] filling systems to isolator contained filling systems.”

“The distinct advantage is that the environment around the open packaging container is sterilized (typically with vaporized hydrogen peroxide [VHP]) with the use of isolator systems,” King specifies. “Isolators cause a bottleneck in regards to small batches as the [process changeover times] can be complex with the requirement to reduce the risk of product contamination from hydrogen peroxide.”

“Ensuring sterility through the manufacturing process is critical and can lead to bottlenecks both for product release and during product changeovers or when there is a temporary issue on the line that is holding up production,” confirms Jenkins. A microbiology team can play a crucial role in helping to minimize such disruptions, he explains, as microbiology considerations can be incorporated at the process design stage and when optimizing operations.

“Sterility assurance is critical for quality control (QC) release of sterile drug products, and the industry-wide approach involves a two-week incubation period—both for testing the drug product and environmental monitoring of the facility,” Jenkins continues. “Numerous rapid sterility testing methods are now commercially available to help address this and can be applied in later stages of development.”

Additionally, supply chain disruptions, which have impacted many global industries over the past few years, can be challenging for aseptic processing, asserts Aimee Hodge, vice-president Business Operations, PCI Pharma Services. “Lengthy lead times for components and drug substance can be very challenging, especially for time critical projects,” she says.

“Delays or disruptions in the procurement of essential packaging materials can significantly impact production timelines and quality assurance efforts in aseptic processing,” states Kappler. “Addressing these supply chain challenges early in a project is crucial to maintaining the integrity and efficiency of the aseptic processing workflow.”

Gaining efficiency through automation

Improving the efficiency of the aseptic workflow is key to ensure critical therapies reach patients in a timely fashion while also being safe and effective. “Automating processes and bringing robotics into aseptic processing, together with single-use systems, [are] helping to streamline processes, minimizing human intervention and reducing the risk of errors or contamination,” emphasizes Hodge.

“Innovations in analytical testing such as rapid microbial and particle detection and rapid sterility testing can save valuable time for releasing drug product to clinical trials or commercial supply,” Hodge adds. “For example, with rapid sterility testing sample results are available in less than seven days, providing time efficiencies when compared to the 14-day incubation required for compendial sterility.”

However, regulatory requirements for viable particulate monitoring are based upon colony forming units, which “cannot easily be directly correlated with fluorescent particle counting results,” Smart asserts. “Manufacturers must be able to validate new methods against the existing standards to demonstrate the new method’s equivalence or superiority.”

Smart points out that rapid micro methods use biofluorescent particle counters in place of settle plates for viable particulate monitoring. “This technology has enormous potential to benefit manufacturers by providing real-time microbial data during aseptic processing,” he says. “Rather than waiting weeks to find out about EM [environmental monitoring] failures, operations can respond to issues as they occur and limit or avert resulting investigations and batch losses.”

“[Another] advancement that is now being more accepted by the regulatory bodies is the use of rapid microbial monitoring systems, [which not only] monitor particles within the filling environment, but also have the capability to determine if the particle is viable or non-viable,” King adds. “If the particle is viable, it is captured real time on a growth medium. This is reducing environmental monitoring excursion identification time frames.”

The presence of particles, subvisible or visible, in parenteral products causes delays and contributes to medicines shortages worldwide, specifies Belinda Holdsworth, strategic growth project lead, Drug Product Services, Lonza. “Having a robust, fast, and reliable method for visual inspection is therefore of utmost importance to drug developers, as well as to their patients,” she says. “An important trend in this space is the utilization of robotics and automated visual inspection (AVI) for defect and visual particle identification in drug products.”

“[Additionally,] the utilization of AI [artificial intelligence] for data analysis [of] image and pattern recognition significantly enhances the detection of difficult-to-inspect parenteral drug products and decreases false reject rates,” Holdsworth specifies. “Combined with an automated robotics approach, this robust process can eliminate the formation of air bubbles, thus greatly enhancing process timelines.”

Focusing on an engineering perspective, Kappler believes that industry will move toward more standardized processes. “In terms of smaller batches, the industry apparently tends to move toward established and validated components such as ready-to-use/ready-to-fill containers,” he says. “This [approach] allows [the manufacturer to] focus on the product core without investing too much time and effort on side processes.”

It has been a decade since ready-to-use pre-sterilized nests of vials were launched by glass pharmaceutical packaging specialist, Schott, explains Jenkins. “These [nests of vials] were designed in collaboration with filling-line manufacturers to eliminate certain processing steps, such as vial washing, drying, and sterilization at the drug product manufacturing line,” he says.

“The nested packaging also reduced incidents of glass vial damage due to vial-to-vial and vial-to-machine contact,” Jenkins states. “This [innovation] paved the way for advancements in robotics and automation, leading to a range of filling solutions, from small-scale support for early clinical supply to more robust systems capable of filling hundreds of vials per hour.”

Further innovation is being seen in the machine manufacturing space that reduces operator interactions, Kappler continues. “Advancements have been made surrounding environmental monitoring that is causing streamlining of operations of critical monitoring steps that ensure that the product remains aseptic throughout the process,” he confirms.

“Advancements in automation and robotics are revolutionizing aseptic fill/finish processing,” confirms Hodge. “From vial loading to stoppering, advanced robotics are streamlining and enhancing the efficiency of sterile fill/finish operations with reduced human interventions, minimizing contamination risks, while optimizing production speed and time to provide life-changing therapies to patients.”

Although, robotics still have some limitations, particularly in responding to faults, jams, and other unplanned events that are not programmable, Smart stresses. “In these cases, there is future potential for use of vision systems and machine learning/AI to provide robotics the capacity for responding to unplanned interventions without the risks inherent in human operations,” he says. “Manufacturers looking to maximize the benefit of robotics and other automation should seek to understand how to maximize flexibility in how they implement these solutions. A set of robotic tooling that is fit to a single format does not provide significant operational advantages over a set of single size format parts in a traditional line.”

Speeding up time-to-market

“Time-to-market can mean the difference between having a viable product or the competing product taking the market,” emphasizes King. “The best way to reduce the time[-to-market] is to have all production activities at one site. If a company can produce the drug substance and drug product at the same site, product testing, storage, and release times can be greatly reduced.”

Managing to get a product to commercialization quicker also helps to provide patients with life-changing therapies in a better timeframe and ultimately improves their health outcomes, Hodge adds. “Biopharma companies can endeavor to accelerate the delivery of their drug product to patients by developing well defined processes and testing methods together with a product road map early in the drug development lifecycle to identify the steps to plan for to advance along the journey to commercial readiness and launch,” she says.

“Contract development and manufacturing organizations (CDMOs) also play a crucial role in supporting the accelerated supply of life changing therapies to patients by providing expert solutions for drug development, manufacturing, and clinical trial services,” Hodge specifies. “When partnering with a CDMO, to ensure a robust supply chain and support speed to market, it is vital that a preferred CDMO has global reach together with flexible, scalable solutions to support clinical trial from early phase through to commercialization.”

For Droc, the use of sterile, ready-to-use, and single-use packaging solutions is valuable when trying to increase product quality and patient safety, and also reduces time-to-market. “From the perspective of drug developers, these solutions can also accelerate time to market by streamlining operations and expediting product development,” he says. “For drug product manufacturing, pre-sterilized containers, such as vials, syringes, and cartridges, that are ready for filling are especially relevant.”

“Flexibility will be another key aspect of future time-to-market aspects,” reveals Kappler. “[Because] the variety of single products during clinic is high, systems that allow switching between different packaging materials, and quick change between different product set ups will increase usage and allow pharmaceutical manufacturers to quickly react on formulation in early phases.”

Although the benefits of reducing the time it takes to commercialize products are obvious, there is also a need to balance leveraging the use of innovative technologies with standard “tried-and-true” practices, Smart adds. “No one in pharma wants to jump in at the ‘peak of inflated expectations’ in the Gartner Hype Cycle, whereas waiting too long jeopardizes potential competitive advantages,” he says.

“While in many ways the [aforementioned] technologies are not new to the industry, their adoption still has far to go,” concludes Smart. “Courage is required to innovate, but the potential gains are significant. Given that regulatory agencies are themselves recognizing the benefits of these technologies, it seems that the way is paved for industry to reap the rewards of implementation.”