Integrating Single-Use Systems in Biopharma Manufacturing

Artifacts Images/Getty ImagesTo gain perspective on the use of single-use systems in biopharmaceutical manufacturing,BioPharm International spoke with Nandu Deorkar, PhD, vice-president of Research and Development at Avantor Performance Materials; Steve Miller, global head of Next Generation System Development, Life Science, Upstream and Systems Business Field Millipore S.A.S; Miriam Monge, director of process development and bioprocess platforms, Integrated Solutions at Sartorius Stedim Biotech; and Dr. Chris Chen, CEO of WuXi Biologics. 

BioPharm: Which manufacturing processes benefit most from the use of single-use systems?

Deorkar (Avantor): Both upstream and downstream manufacturing processes benefit from single-use systems, particularly when manufacturers are producing buffer solutions or cell-culture media. Single-use systems reduce the time required to perform cleaning and cleaning validation. They also allow manufacturers to more easily—and quickly—turn over from one product to another, or from one batch to another batch. In addition, single-use systems can connect two unit operations, thereby minimizing hold time and enabling continuous processing. Finally, single-use systems are shown to reduce overall operating costs by minimizing or eliminating the need for clean in place (CIP)/sterilize in place (SIP), reducing analytical quality control costs—specifically for raw materials—and improving facility utilization time.

Miller (Millipore S.A.S): The main drivers for single use have altered little over the past 10 years. The processes benefiting most have issues around contamination and cleaning, reducing water consumption, ability to run multi-molecules in the same facility, and small-scale commercial production with low numbers of batches per year.

Monge (Sartorius Stedim Biotech): All those processes that require 1000 kgs per annum of product or less and can be manufactured in single-use bioreactors up to 2000-L scale or less can benefit enormously from working in single-use systems. Single-use [systems] offer increased flexibility to adapt to a wide variety of different processes at different scales coming through the pipeline. Single-use systems also enable increased productivity and reduced cost of goods. There are many end-user case studies out there to prove this is the case. 

Antibodies, proteins, vaccines, cell therapy, and gene therapy all fall into categories of molecules that can benefit from being manufactured in fully single-use, end to end processes. 

Chen (WuXi Biologics): Production scales between 15 L to 2000 L can all benefit from the use of single-use systems. Traditional fed-batch cell culture process as well as perfusion processes can be easily implemented in single-use systems. WuXi Biologics, an open-access R&D capability and technology platform company dedicated to biologics and a WuXi AppTec company, has embraced single-use technologies at full steam since 2010. The rapid adoption of single-use technologies has enabled us to quickly build up and expand our production capacities.  As a contract development and manufacturing organization, single-use technology allows us to significantly reduce capital cost and facility construction time and increase running rate by quick turning-around between different products and eliminating cross-contamination risks. 

BioPharm: What measures should be taken when ensuring system compatibility between single-use systems? 

Chen (WuXi Biologics): Different single-use products could have significant differences on design details, which might pose different degree of challenges when it comes to system compatibility between products from different suppliers. For example, agitation/mixing and gas sparging designs are quite different among the single-use bioreactors from the several major suppliers. The end-users need to carefully understand and evaluate the design features of the various products. The same challenges exist between single-use system and the stainless-steel systems. Process transfer using the actual production cell line and processes must be carried out to ensure system compatibility, with special attention on potential product quality impacts. Another challenge for a single-use bioreactor system is the lack of reliable scale-down model. Representative scale-down models of single-use bioreactors are typically at 50L scale, which is too expensive and also not practical/convenient to use. 

Miller (Millipore S.A.S): Implementing single use brings with it new challenges that traditional facilities do not face, such as ensuring skids from different vendors have compatible connectors and common spare components such as clamps. Other, lesser-known challenges are related to packaging, installation and disposal, as each manufacturer may have different approaches, making operator life more complex and introducing opportunities for more errors.

Deorkar (Avantor): Single-use system components are typically made using flexible polymer films or plastic. Because of this, you need to make sure there are no extractables or leachables, which could impact cell growth, coming out of the system. These issues can impact product yield, quality, or stability. More importantly, you should evaluate the equivalency of the yield and the product quality coming out of the single-use system versus a stainless-steel system. If there is a difference between the cell growth in the stainless-steel versus single-use systems, you might see a difference in product, yield, and quality. 

Monge (Sartorius Stedim Biotech): There are certain connectors that have become pretty standardized across the different suppliers, so connectivity between different single-use systems is not really an issue today. When talking about connectivity between single-use and stainless (in the case that a hybrid process design has been selected), autoclavable stainless-steel systems can be connected to single-use systems with a sterile connector, such as the Opta from Sartorius. The Opta is autoclavable and can be connected to a stainless-steel vessel and then autoclaved together with the vessel. This vessel can then be connected to a single-use system equipped with the Opta counterpart. 

BioPharm: Have you seen any specific challenges in compatibility between single-use systems? 

Monge (Sartorius Stedim Biotech): One of the challenges when testing single-use systems is that you need to compare the different testing methodologies used by the different suppliers. This is the case for extractables and leachables, pre-use and post-use integrity testing, and visible and non-visible particulates. It is not always easy to compare like with like.

Deorkar (Avantor): The long-term storage of solutions, such as buffers or cell-culture media, in single-use systems can generate extractables and leachables, which may cause impurities. One way to address this challenge is to prepare buffer or media on an as-needed basis by using solid materials that are customized for one single-use tank, rather than concentrated buffer solutions that are already in liquid form. We have provided customers with single-use powder materials in bags or other containers that are pre-weighed and compatible with single-use systems. The packaging that contains the solid can be attached directly to a tank and the biopharmaceutical manufacturer can then make the solution, avoiding the long-term extractable/leachable compatibility issue.

BioPharm: What should be considered in regard to media and buffer selection when using single-use systems?

Monge (Sartorius Stedim Biotech): It is very important to review what tests are being carried out on the single-use systems and to which industry standards they comply. For example, at Sartorius we are aligning our testing methodologies with the industry standards that are identified as creating the greatest consensus in the industry both by suppliers and industry end-users and are recognized by the regulatory authorities. In this context, we are engaging actively notably with the American Society for Testing and Materials (ASTM) E55 working groups (E55: Manufacture of Pharmaceutical and Biopharmaceutical Products) developing standards for extractables and leachables, integrity testing at vendor factory and at end-user site, particulates at vendor factory, and at end-user site and cell growth.  

When thinking about selection of single-use systems and films for media, the cell growth issue is of particular concern. Here we have proposed the development of a new standard assay assessing the suitability of specific plastics for cell growth applications in single-use. Recent industry reports demonstrate that current biocompatibility testing did not always detect cell growth issues. The discovery of a cytotoxic leachate raised industry awareness of the need for new evaluation techniques and testing to determine potential impacts of plastics used in single-use systems on cell culture plastics

Deorkar (Avantor): Before making a media or buffer selection, manufacturers should discuss packaging options with their materials suppliers. Often, the composition of packaging films in which a material is supplied is just as important as the material itself, because the packaging can impact the quality of the product.

Manufacturers should consider the impact that different buffer solutions or cell-culture media may have on the integrity of the single-use component—bags, for example—in which they are supplied. For example, some packaging for liquids supplied for single-use systems may not be 100% impermeable to air. This could change the buffer pH, conductivity, or stability of some solutions. By seeking out a supplier that can provide pre-weighed solid materials in packaging that is compatible with single-use equipment, manufacturers may be able to avoid this common issue. This type of packaging may also eliminate time-consuming material subdivision and kitting steps, which can reduce total cost of ownership, improve efficiency, and reduce the potential for contamination.

BioPharm: What steps should be taken when validating suppliers?

Miller (Millipore S.A.S): There are many similarities to validating suppliers of traditional equipment: checking that the proposed equipment matches the process and is compliant with regulations and surface contact compatibility. What is different is that choosing single-use equipment is the beginning of a multi-year relationship between the customer and the supplier. Therefore, ensuring the supplier’s commitment is more akin to a filter purchase than a system purchase. Assessing the supplier’s process know-how, supply chain, manufacturing processes, support organization, and field force are much more important.

Another big difference for single-use versus traditional technologies is the importance of evaluating all scales of equipment, even if the procurement exercise is for the small scale only. A technology may work fine at a 50-L scale; however, when you scale to 2000-L processes, ergonomics and process robustness/optimization become a huge factor in the commercial operation. The difference with single use is that customers can be stuck with the technology they chose at the small scale and the conversion to alternative suppliers, even if there are significant advantages at the large scale, are too big a risk on the timeline to consider switching. 

Monge (Sartorius Stedim Biotech): This is best verified through a supplier quality and supply chain audit. This includes reviewing the supplier quality system and manufacturing systems and ensuring that these are cGMP compliant. Ensure that the level of compliance is consistent across supplier sites, check the manufacturing environment in which the single-use systems are manufactured (ISO class 7 manufacturing environment for single-use systems is what the majority of end-users specify as a requirement), verify customer change notification process, and complaint management process.

Another important part of your single-use supplier audit includes supply chain security to ensure that the supplier has the systems in place to ensure delivery performance and offer best assurance of supply and business continuity.

BioPharm: What are the challenges of qualifying single-use equipment? 

Miller (Millipore S.A.S): The challenges here are making the process robust. Qualifying the perfect scenario is easy, but anticipating damaged or dropped assemblies, qualifying how assemblies move from grey to clean space, and disposal are all exaggerated versus traditional facilities.  These challenges can be minimized by ensuring equipment and assemblies come from the same supplier, as they should have qualification procedures as part of the total solution.