Single-use technology, designed for the manufacturing of biopharmaceutical products, has made major inroads over the last 30 years. First introduced in the late 1970s in the form of disposable capsules and a range of filters, single-use technologies were revolutionized in the late 2000s with the introduction of single-use 2D and 3D process containers and filter assemblies for mixing and storage systems. Today, these technologies have been adopted across the upstream manufacturing process, downstream purification and fill-finish of entire classes of biologic drugs.
The adoption of single-use technology is especially growing in the development and manufacturing of biologics and complex drugs like Antibody-drug Conjugates (ADCs).
Antibody-drug conjugates
ADCs are highly potent biopharmaceutical drugs designed as a targeted therapy in the treatment of cancer. They are highly hazardous materials, often with occupational exposure limits (OEL) below 100ng/M³/8Hr work day.
The acute potency of ADCs creates a significant risk to personnel involved with the various manufacturing stages. The accepted method to counter the risk of exposure to ADCs is the implementation of so-called barrier isolation systems. These systems are recognized as the highest level of current containment technology, creating both respiratory and dermal protection.
While the use of glass or stainless-steel legacy systems may effectively protect operators, significant equipment decontamination is required. Since most ADCs are produced on a small (production) run/campaign with manufacturing typically taking days rather than months, the cleaning validation burden associated with a hard-shell glass or stainless-steel isolator can be an issue.
Alternative to traditional technology
“Single-use technologies are an alternative to traditional glass or stainless-steel manufacturing with the key difference in their materials of construction. Glass and stainless-steel equipment have decades of historical data and, as a result, their use is well characterized,” noted Karen Green, product manager for single-use assemblies at MilliporeSigma.
“Single-use systems are commonly composed of polymeric materials, which are not as well-known or characterized for biologics processing. These differences result in different approaches to validation and qualification,” she added.
Figure 1.0 A typical ADC process work flow. The input mAb is prepared into reaction conditions by simple dilution or through buffer exchange by ultrafiltration/diafiltration (UF/DF), a very economical, high-yield and robust separation process. In the processing equipment, the antibody will be further modified, then conjugated with the drug linker to form the crude ADC.Benefits
In the manufacturing of highly complex active pharmaceutical ingredients (APIs) such as ADCs, single-use technologies offer specific benefits in the upstream manufacturing and production of monoclonal antibodies (mAbs) and downstream bioconjugation.
For example, single-use technology enables faster process changeover and facility flexibility that is not possible when traditional equipment is used.
“Since each single-use system is pre-sterilized and used only once, there is no need to sterilize or clean systems between batches, saving time and enabling manufacturers to produce multiple products within the same facility. Furthermore, single-use systems are often mobile, allowing them to be moved within the facility as needed, enabling additional facility flexibility,” explained Mary Robinette, principal project engineer at MilliporeSigma.
Contract development and manufacturing organizations
According to various reports, 70-80% of the manufacturing of ADCs is outsourced to contract development and manufacturing organizations (CDMOs).[1]
“Due to [this] increased outsourcing pattern, CDMOs entertain many different types of ADCs. The use of single-use technology by CDMOs will help speed up the product change over time, avoiding time spent in establishing cleaning methods for each product that is produced, and eliminating upfront investment for expensive capital equipment such as reactors for each product,” said Gang Yao, Ph.D., principal scientist, process & analytical development at MilliporeSigma.
“In the end, customers benefit from lower manufacturing costs and speed to market. The faster turnover will result in more batches made to meet the commercial demand,” he added.
Implementation of single-use technology
Single-use technologies have advanced in several ways over the past decade. Their materials of construction are better known and have established leachables and extractables profiles, and manufacturing techniques have evolved leading to cleaner and more robust films.
Due to these advancements, the adoption rate of single-use has steadily increased across the biopharmaceutical industry, including ADC manufacturing. However, ADC manufacturers will need to be assured of solvent compatibility with bag liners and other single-use components since the manufacturing of ADCs often involves either dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA) for the conjugation process.
They also will need to trust that the potential for a leak during the conjugation process is extremely low and that they can successfully scale from a smaller development scale to large-scale GMP production.
Single-use technology suppliers, like MilliporeSigma, have recognized these concerns and have demonstrated that the materials in single-use technologies are indeed compatible with two commonly used solvents (DMSO and DMA) at the temperatures and duration typically used for ADC processing.
Addressing the aggressive conditions used during bioconjugation to ensure compatibility with the polymeric materials used in single-use assemblies and understanding extractables and leachables under these conditions are vital. MilliporeSigma provides supporting data to ensure that the use of solvent during the manufacturing process will not negatively impact the conjugate by demonstrating solvent compatibility as well as sharing representative leachable and extractable data.
MilliporeSigma also has demonstrated that small-scale development batches can be successfully scaled up to large-scale GMP batches using a completely single-use process, guaranteeing operator safety at all steps in the manufacturing. In this single-use process, the fluid contact materials do not change, only the size of the components of the process assemblies. “However, operator safety becomes very critical with the use of more potent linker payloads that typically demonstrate IC50 values in the low-to-mid picomolar range,” Yao added.
Tangential flow filtration
Tangential flow filtration (TFF) is a common unit operation in ADC manufacturing and enables concentration and exchange to pre-formulation buffer.[2]
The presence of toxic linker-payloads following conjugation presents challenges in traditional TFF operations. The scale of TFF also can be a challenge.
“MilliporeSigma has developed a completely enclosed single-use TFF capsule. This device is shipped gamma sterilized with RO (reverse osmosis) water, which reduces flushing requirements and enables faster batch turnaround while utilizing the same Ultracel 30 kDa membrane found in our traditional flat-sheet devices,” noted Nicholas Landry, group product manager ultrafiltration at MilliporeSigma.
“The device was engineered with operator safety and containment in ADC processes as design principles,” he added.
Upstream and downstream processing
While single-use technology has generally been used in upstream processing in the manufacturing of mAbs, the technology is now also available in downstream bioconjugation.
One of the major benefits of single-use technology in downstream processing is bioburden control. Single-use technology offers a more closed processing opportunity compared to traditional glass or stainless-steel reactors, thus reducing the opportunities for bioburden growth.
Another significant benefit of single-use technology is that there is no cross-contamination from inefficient cleaning, allowing faster turnover between process changeovers in a biopharmaceutical manufacturing facility, while at the same time, reducing cleaning validation requirements.
In the final verdict, single-use technology has proven, compared to traditional methods, to be a flexible, cost-effective and efficient alternative that provides improved safety. There is no cross-contamination from inefficient cleaning and no cleaning required between batches, resulting in a quicker turnover of the facility.
Reference
[1] Roots Analysis, Antibody Drug Conjugates Market (2nd Edition), 2014 – 2024.
[2] Czapkowski B, Steen J, et al. “Trial of High Efficiency TFF Capsule Prototype for ADC Purification,” ADC Review, April 12, 2017. [Article]
Last Editorial Review: April 5, 2019
