In this webinar, Scott Patterson, Vice President of Technical Support at ILC Dover, looks at modern containment solutions for handling small molecule oral solid dosages in-depth. With a focus on advanced flexible film single-use isolators, Scott explores strategies for achieving high containment levels, reducing cross-contamination risks, and streamlining operations. The session delves into the evolution of containment technologies, the importance of adaptable designs, and the practical benefits of using flexible isolator systems.
Watch the video or explore the transcript below to learn more.
Transcript
Introduction
[Scott Patterson] 0:01
Welcome to the ILC Dover webinar series. This presentation will focus on modern containment solutions in small molecule oral solid dosage handling processes. I’m Scott Patterson, your presenter today and Vice President of Technical Support at ILC Dover. Our presentation will take you through the “as is” paradigm of past containment philosophy and into the “to be” concepts when applying state-of-the-art flexible film single-use isolators.
Here’s a great analogy using Coca-Cola and the “to be” concept: Imagine in 1886, a pharmacist named John Pemberton invented the syrup for Coca-Cola. Do you think he would have ever imagined 135 years later that a bottle of water would be more valuable than his syrup mixed with water? In most stores I go to, at checkout, the individual bottles of water are the same or higher in price than Coca-Cola. This analogy is used in our containment philosophy when we’re thinking about making water for injection for cleaning, the labor for cleaning, and the significant disposal costs. So, let’s get started.
The Changing Containment Landscape
[Scott Patterson] 1:16
There’s a changing landscape in the containment world for oral solid dosage processing. We look at some of the past drivers and the current situation. In the past, there was master site planning over extended periods, often 10 or 20 years, about what a site would do. Now, we have very short-range production planning, three years at most in many cases, and we follow a lot of the CMO model for multiple-use products in a facility. We’ve seen this model use up to 60 molecules in one facility in one year.
About 10 years ago, the high bar for containment was one microgram per cubic meter, determined on a time-weighted average (TWA). That’s no longer the case; we’re now looking at HP APIs with tolerances 10 times stricter, at 0.1 micrograms per cubic meter, and not a TWA. The original containment strategy focused on operator exposure, but now it also includes mitigating risk for cross-contamination.
Previously, there was central manufacturing and tonnage. Now, with global manufacturing sites, we’re looking at smaller batch sizes and more changeovers, which need to be more efficient and quicker. We see this as we look at the two isolators at the bottom of the page: the past hard-wall isolator concept and the future flexible isolator concept.
Containment Designs Need to Be Adaptable
[Scott Patterson] 3:03
Containment designs for modern applications need to be adaptable. On the right, we have an analysis from a consulting firm specializing in stainless steel facilities and single-use or flexible film isolator facilities. We found that stainless steel facilities are capital-intensive, with long build-out times of up to five years. Interestingly, facilities often don’t produce what they were designed to do because the business model changes, possibly taking on new molecules or different processes. Additionally, sales forecasts in the pharmaceutical industry can be very inaccurate over three years.
In a real-time application shown on the left, an order was placed for a flexible isolator system intended for a weigh-in dispense process. However, during the build-out, the design was reconfigured to package the API for stability trials. Because we leveraged modern flexible isolator technology, we delivered the system on time and under budget, which would have been impossible with traditional stainless steel and glass technology.
The past technology required a mock-up when designing isolators, a tradition where layout and dimensions had to be precise to avoid significant costs and delays. SOPs needed to be worked out in advance, and the size and weight of materials and tools had to be perfectly laid out to avoid ergonomic issues. However, even with perfect mock-ups, ergonomic issues, and process changes often led to problems.
The Modern Experience – Nimble Design Process
[Scott Patterson] 6:12
In the modern experience, there’s a more nimble, iterative design process. For example, in a tablet press containment design, we start with the basic press, create the containment zone, position operator gloves, and add a transfer isolator for analytical evaluation. This iterative design process allows for minimal changes to SOPs and provides a seamless transition from non-contained to contained operations.
Modern designs also allow for changes post-installation, such as adding or moving glove locations or sample sleeves. For instance, a high-flow static HEPA filter was added to address airflow issues, improving overall containment without significant cost or delay.
Modern Flexible Containment Designs
[Scott Patterson] 8:07
Modern flexible containment designs include examples like a single frame used for two isolators, adapted for different processes by changing the flexible film. The frame design accommodates multiple uses, particularly with transfer systems like bag-in/bag-out, enhancing containment. For example, one frame can support a weigh-in dispense application and another for a ROTAB system during the ROTAB process, demonstrating the flexibility of film isolator technology.
Daisy Chain Isolator Capability
[Scott Patterson] 9:13
The daisy chain design allows for working in a single-unit flexible film isolator or combining two or more isolators for continuous workflow. These isolators can be purpose-built for unit operations, such as milling or tablet processing, and connected to minimize labor and transfer material risks. This system enhances containment and process efficiency.
Deploy the Containment System Only When Needed
[Scott Patterson] 9:54
Modern containment design also allows for deploying the containment system only when needed. For example, after dispensing into a carboy, the isolator can be removed, and the frame folded and stored efficiently. This approach reduces the need for cleaning and conserves valuable processing space.
In roller compactor designs, integrating the containment flange mounting makes systems high-containment ready. Flexible isolators can be deployed as needed, offering OEB4 or OEB5 containment levels and additional protection during critical processes.
OSD Workflow – Example of Wet Granulation
[Scott Patterson] 10:38
Flexible containment systems are designed to be adaptable across different workflows, including wet granulation, dry granulation, spray drying, and hot melt extrusion. They facilitate the containment of unit operations and transfers, ensuring comprehensive handling and safety.
Case Study – OSD Dry Granulation Workflow
[Scott Patterson] 14:57
In an actual case study of a CDMO formulation lab, the customer scenario involved expanding capabilities to handle HP APIs, aiming to increase sales and revenue. The project required a 20-week timeframe for implementing the containment system and proving performance to new clients.
The strategy involved applying retrofit designs to existing equipment, leveraging flexible film isolators to meet the delivery deadline with minimal hardware changes. A robust surrogate test using the ISPE SMEPAC protocol was performed to ensure containment performance, targeting 125 nanograms per cubic meter.
OSD Case Study – Weigh and Dispense
[Scott Patterson] 17:01
In the weigh-in dispense process, which included manual sieving of API, the flexible film isolator achieved excellent results, with less than seven nanograms per cubic meter containment across three test runs.
OSD Case Study – Roller Compaction
[Scott Patterson] 17:45
In the roller compactor and granulator process, the isolator achieved less than 14 nanograms per cubic meter containment. The results highlight the impact of various factors on containment, such as process type, material characteristics, and transfer operations.
OSD Case Study – Encapsulation
[Scott Patterson] 19:17
In the encapsulation process involving granulated product, the isolator achieved less than three nanograms per cubic meter containment, with one outlier at five nanograms per cubic meter. This demonstrates the variability in containment levels depending on the process and material properties.
OSD Case Study – Results and Highlights
[Scott Patterson] 20:33
The case study results showed the containment performance met the target of less than 125 nanograms per cubic meter, except for one instance at the blender due to a connection left open, which was later corrected. The design process eliminated the need for a mock-up, and flexible isolator design updates based on operator feedback were implemented without delaying production. The average isolator system cost was under $65,000, with minimal equipment modifications, leading to significant cost avoidance.
OSD Case Study – Customer Journey “As Is” Then “To Be”
[Scott Patterson] 23:18
The customer’s journey from “as is” to “to be” involved transitioning from traditional hardware to modern flexible isolation technology, streamlining production, and boosting capacity. The project avoided significant capital expenditure, amounting to $1.4 million in cost avoidance, and demonstrated potential for substantial operational savings compared to stainless steel solutions.
Customer Experience #7 – Execution Excellence
[Scott Patterson] 25:12
The customer experienced execution excellence, with the flexible film system allowing for timely product launch and market capture. The flexible system was delivered at a fraction of the cost of a hard wall system, with comparable performance and significantly reduced cleaning requirements.
Customer Experience #2 – Eliminate Large CapEx and OpEx
[Scott Patterson] 26:39
The case highlighted significant capital and operational expense savings. The flexible film system costs about $55,000, while the hard wall system costs approximately $725,000. The flexible system required minimal cleaning and modifications, leading to efficient production and market entry.
For more information, please contact ILC Dover.
