Single-Use Process Systems

The pharmaceutical industry’s appetite for single-use technologies and information on effective usage of them is one of the fastest-growing industry trends. Disposables are in use in over 90 percent of pharmaceutical and biotechnology companies’ manufacturing processes. While the core benefits of single-use technologies are well-documented (1), there is need for more knowledge on implementation and usages. Among these points are integration of multi-component disposable systems, scalability, increasing economic benefits, extractables considerations, disposable facility design, evolving industry guidelines, and new manufacturing models.

Industry Overview

Recently, the Bio-Process Systems Alliance (BPSA), an industry initiative under the auspices of the Society of the Plastics Industry, introduced component quality test matrices for each single-use system subcomponent class (2, 3). These matrices, the first in a series of guides being developed by BPSA, provide quality test methods and list consensus reference documents along with testing frequency guidelines to help users select, qualify and validate disposable systems and components. Future guides will address issues including other single-use system components, sterility claims, extractables and leachables, and system-based issues.

The industry is also coming together to explore the challenges and advantages of disposable processing. This has resulted in a large number of recent meetings and conferences dedicated to these issues, and many other industry conferences concerned with production and process development issues have included segments on single-use processes. Some of the most talked about subject areas include the increase in multi-product facilities, manufacturing of personalized medicines and vaccines, converting to single-use technologies, accelerated production in developing countries for export, and the use of disposable technology in animal health.

Understanding Time and Cost Savings

Because there is a wide range of both hard and soft economic benefits associated with disposables, the complete cost savings picture can be different from manufacturer to manufacturer. For example, while the elimination of cleaning and cleaning validation is commonly seen as a significant source of time and labor savings, the absence of these procedures also minimizes or removes the need to buy and maintain costly utilities, such as Water For Injection (WFI) systems. In the case of pre-sterilized disposable technologies, the need for boilers, clean steam generators and Steam-In-Place (SIP) systems is also eliminated. The reduction or elimination of stainless steel processing equipment and utilities translates into further savings by minimizing space requirements.

In order to truly understand the benefits of disposables, one must look at each manufacturing situation individually. For example, vaccine manufacturers will realize different benefits from those of biotech start-ups or contract manufacturing organizations (CMOs). Similarly, a drug company seeking to retrofit a facility with disposables will measure time and cost savings differently than one that is building a new “disposables factory.”

Efficient Facility Design Results From Adopting Single-use Processes

More than just the sum of its benefits, disposable processing represents a fundamental change in processing approach and facility design. As a closed loop system, disposable processing avoids the need to disassemble, transport, clean, validate, and reassemble components in classified cleanroom environments. In many cases, disposable products are supplied pre-sterilized (by gamma irradiation) to eliminate the need for Steam-In-Place (SIP) or autoclave sterilization procedures and the equipment maintenance costs associated with these. Opening a package and plugging a single-use device or multi-component disposable system into a product train is a welcome simplification to process development staff members who would otherwise need to develop extensive cleaning protocols. The result is not only labor savings, but also a shift in facility design toward fewer cleanrooms and reduced environmental monitoring.

With disposable operations, applications no longer need to be physically segregated. Instead, they can be performed side-by-side in closed loop systems. This makes more efficient use of facility space, especially beneficial for CMOs and biotech start-ups. At the same time that disposable systems seal off processes from contamination, the translucency of integrated components provides operators with convenient visibility into manufacturing operations. Users can observe fluid levels and flow and immediately spot fluid discoloration and air pockets.

Disposable processes also allow for a high degree of modularity and in that capacity can be built out gradually in phases as demand increases. Within conventional facilities, it is not only the hard-piped systems themselves that need to be factored into the initial facility design, but also the over-sized utility systems in anticipation of future needs.

The modularity of disposable components also facilitates retrofitting, making it significantly easier with disposables than with fixed equipment, For many of the same reasons, disposables simplify transfer of the drug production processes to other manufacturing sites, such as CMOs, or other facilities within a company. The ability to easily duplicate production processes makes overseas manufacturing particularly economical for multinational companies.

Without requiring the significant capital investment needed with hard-piped systems, disposable technologies have empowered biotech start-ups to manufacture in-house. This gives them more control over the development process and enables production to be accelerated as needed. Previously, outsourcing production was the only economical option. The new flexibility affords companies to better manage their manufacturing expenses and investments during the development stages, when the requirement for greater drug supply in advanced clinical trials can still carry considerable risk of product failure.

Disposable technologies provide greater flexibility in terms of system size. System upgrades are feasible as newer technologies become available. It is also easy to add capacity by manifolding disposable components in series or parallel configurations. The equivalent additions in a hard-piped system would involve welding a new tank or filter housing into the system.

Perhaps the most compelling reason to adopt disposable processing methods is the reality that any possibility of cleaning errors or potential carry-over residues from batch to batch is eliminated. Not surprisingly, the FDA in their oversight role ensuring risk avoidance in the industry has always been a major proponent of disposable processing. Considering that validation accounts for 10 to 20 percent of the cost of a new plant, disposables suppliers share the FDA’s sentiment to provide practical solutions to the industry to alleviate the challenges and costs associated with cleaning operations (4).

Application-Specific Benefits

Containment and operator safety issues for high-potency formulations or biologically toxic compounds, such as new vaccines and cancer therapeutics, are also driving increased use of disposables. This is because disposables minimize operator exposure to strong compounds by eliminating disassembly and cleaning. While operator risks associated with small molecule and synthetic drugs are significant, the hazards of working with live viruses in vaccine production are greater still. In addition, disposable components are typically lighter than equivalents used in hard-piped systems, making operator handling easier and safer.

Scalability and Validation

The cost- and time-saving benefits of disposables are also a function of scalability. Because disposable products are available in a range of sizes, they are ideal for use at every stage of drug development, from discovery to production. Single-use products that use the same materials of construction minimize re-validation requirements as a new process is scaled up. This also helps ensure that scale up and scale down studies yield relevant information.

Therefore, selection of the most appropriate filter media, materials of construction, and system configuration at the process development stage are crucial since the selection process will dictate the type of technologies that will be used throughout process development and production. For example, by using scalable filtration product designs and materials, membrane discs and syringe filters can be scaled up to small capsules, and ultimately, large fully-integrated single-use filter installations with minimal process variation.

Scale-up considerations for ion exchange chromatography applications are similar to those of filtration applications. Ion exchange membrane adsorber materials should correspond to scalable capsule and module designs, while maintaining a constant bed height from pilot to manufacturing scale.

The use of consistent filtration media minimizes the need for re-validation as processes are scaled up. If membrane type differs from one stage to the next, drug developers will need to re-validate each time a new membrane is used. This increases the time, labor and costs associated with process development.

By using the same materials of construction (MOC) throughout process development, pharmaceutical companies can enhance efficacy and minimize variability in the final products. Consistent MOC also allow flexibility in the type of housing used. For example, a filter with the same MOC can be used in a disposable or stainless steel housing. This gives drug manufacturers the flexibility to convert from stainless steel equipment to disposable filtration systems while avoiding the complexities normally associated with adopting new processing methods.

The availability of a variety of capsules for small-scale operations is especially beneficial for new product development. Since all new biopharmaceutical products may not become commercialized, capital investment can be a concern. Single-use capsules and systems make it possible to produce new products during the early development stages without a large capital investment. Together, these factors can streamline drug development to increase manufacturing capacity while meeting validation requirements.

Making the Transition from Stainless Steel to Disposable Filtration Systems
Conversion from stainless steel equipment to disposable filtration systems avoids the complexities normally associated with adopting new processing methods by virtue of the fact that both designs use the same filter. The point of differentiation – the filter housing – does not influence the outcome of the filtration. As such, scale-up studies conducted for stainless steel systems can be accurately applied to their disposable counterparts.

The biggest factor in scaling up stainless steel systems that have been retrofitted with disposable products is process development. This involves outlining the processes, products, technologies and services that will be required at each stage, from development to production. Since disposable products exist for every scale of development and production, scaling up single-use systems will be easy provided that parameters such as filter media, materials of construction, flow rate, throughput and differential pressure have been accurately modeled for the original hard-piped systems.

Capacity Limitations

While disposables offer significant scalability benefits in terms of the ability to gradually build out operations as processing demand increases, capacity limitations can prevent their use in certain applications. For example, bag strength is a limitation across all disposable applications that require fluid to be collected in a non-rigid plastic medium. Process bags are reported to be limited to 2,000-liter volumes and 5,000-liters for storage vessels (5). There is also a certain discomfort with disposable bags as processes are scaled up to larger volumes because there is a greater risk that the material will fail due to physical limitations.

However, what disposable technologies lack in size, they make up for in volumetric throughput and productivity. Many disposable technologies have been shown to outperform their stainless steel counterparts, enabling manufacturers to use smaller batches to achieve the same quantity/time ratio. Patient-specific therapies, either cellular or protein-based, gene and viral therapy, and radioimmunotherapy, can all be prepared in small batches ideally processed with single-use technologies. The success of these therapies will be an important factor in driving wider scale adoption of disposables.

Biocompatibility Issues

For all of their advantages, single-use technologies do pose some challenges in the area of biocompatibility. While disposable products are constructed of biologically inert materials with low extractables, which are defined as potential solutes derived under worst-case conditions from the drug product or process fluid contact materials, even trace amounts may need to be addressed in specific cases. Likewise, drug makers run the risk of losing product to the surface of the device through non-specific adsorption. Because extractables and adsorption tests must be performed for each product and application, they can be very time- and labor-intensive. If there is a last minute change in raw materials, repeating such tests could cause serious program delays.

Ideally, drug manufacturers should look for USP Class VI tested disposable products with low extractables, but also be familiar with the lower classifications as well. Materials such as polyethersulfone (PES), polyvinylidiene fluoride (PVDF), nylon and stabilized polypropylene are well-suited for disposable applications because they exhibit low extractables and can be pre-sterilized by gamma irradiation. In addition, biocontainers that use advanced films can reduce extractables and leachables (contact material solutes that are actually detectable in product or process fluids) to a very low level, while providing broad chemical resistance and effective oxygen barriers.

Fully Integrated Disposable Systems

Integration and customization are becoming increasingly pressing topics as single-use technologies continue to expand from stand-alone devices to multi-component systems. While pre-assembled disposable systems containing filter elements, tubing, bags and connection devices have become commonplace in biopharmaceutical manufacturing environments, the ease with which these components can be customized varies from supplier to supplier. For example, Computer Aided Design (CAD) software can be used to give drug companies unprecedented flexibility in designing and building complex disposable systems. This software enables drug makers to quickly and easily envision entire disposable systems before they are built. This can also accelerate the implementation timeline for disposable systems, which are generally installed about 5 times faster than stainless steel systems.

The availability of an increasing number of disposable components also greatly affects the flexibility of the system. For example, new sizes of disposable connection devices allow tubing to be used more interchangeably. Similarly, systems which previously have only been available hard-piped, such as those used for Tangential Flow Filtration (TFF), are incorporating more disposable components with all-plastic fluid paths within an external non-wetted metal pressure barrier to increase the economics and flexibility of this equipment. TFF capsules which require no external hardware are also now being launched for certain applications, such as clarification of fermentation broths.

Disposables: The Universal Solution

Ongoing globalization, revolutionary technological breakthroughs, and government regulation and deregulation have consistently affected the pharmaceutical landscape in recent years. The overriding concerns of the biotechnology and pharmaceutical industries are regulatory and compliance issues, insufficient manufacturing capacity, and addressing the economic challenges of producing niche drugs and therapies.

Disposable systems reduce possibilities for non-compliance and thereby decrease the potential for FDA rejection. They improve the economic feasibility of producing niche drugs by enabling faster, more cost-effective product changeovers. Similarly, demand for low-cost vaccines, including those used for biodefense, can be cost-effectively met through the use of disposable processing methods. Disposables are also an economical fit for offshore manufacturing especially in multi-product equipment trains used to develop biogenerics.

Disposable systems ease the manufacturing capacity crunch by simplifying scale-up, eliminating process steps, facilitating FDA reviews, maximizing throughput, and speeding product changeovers. These factors help manufacturers produce more drugs in less time, and to respond nimbly to a dynamic marketplace.

Since the first single-use product for biopharmaceutical manufacturing was introduced some 30 years ago, there has been a steady stream of new innovations in disposable processing. From disposable filling lines to ion exchange chromatography membranes that provide better flow rates, higher capacities and sharper resolutions many of the industry’s greatest challenges will continue to be overcome with breakthrough single-use technologies.

References

1. E. Langer and J. Ranck, Disposables Economics: The ROI Case — Economic Justification for Disposables in Biopharmaceutical Manufacturing October 2005 BioProcess International Vol. 3, Supplement 6: pp 46-50
2. Part 1, Bio-Process Systems Alliance Component Quality Test Matrices
   BPSA Guidelines and Standards Committee
   April 2007 BioProcess International Vol. 5, No. 4: pp 52-67
3. Bio-Process Systems Alliance Component Quality Test Matrices
   Part Two: Tubing and Filters
   BPSA Guidelines and Standards Committee
   May 2007 BioProcess International Vol. 5, Supplement 4: pp 16-23
4. G. Hodge, “Disposable Components Enable a New Approach to Biopharmaceutical Manufacturing,” March 2004, Biopharm International (online at:
   http://www.biopharminternational.com/
   biopharm/article/articleDetail.jsp?id=87975
   &sk=&date=&pageID=3)
5. A. DePalma, “Throwing it All Away,” April/May 2004, Pharmaceutical Manufacturing (online at: http://www.pharmamanufacturing.com/articles/2004/27.html)