Michael Felo is applications engineer consultant at EMD Millipore.

Michael Felo

Single-Use Technology—From Evolution to Revolution

Single-use technologies continue to evolve rapidly as more biopharmaceutical companies embrace the concept and start implementing single-use systems in their bioprocesses.

It would be hard to overstate the impact that single-use systems are having on the biologics manufacturing industry. What started off as a tool for small-volume solution storage and transport has now become the central, enabling technology around which manufacturing processes and facilities are being designed. Several developments in the industry are driving this change. Within development laboratories, scientists have pushed product titers in cell cultures to levels that are commonly 20-fold higher than those realised 15 years ago. 

Biosimilars (i.e., follow-on versions of innovator biologic products that are at or near patent expiry) offer the opportunity for companies to commercialise products in a condensed timeline for an existing patient population. Given the enormous revenue of some innovator products, the ability to win even a small share of the existing market or open up new markets can be a rich reward to the biosimilar producer. Further, the desire of many governments to have “in-country, for-country” manufacturing of drugs for their population has created the need for smaller, light-asset production facilities designed to meet the local demand.

These developments have driven focus to the 2000-L single-use bioreactor as the centre piece of future manufacturing strategies. The productivity of the current 2000-L single-use bioreactor meets or exceeds that of the 20,000-L stainless-steel bioreactor of legacy processes, with all of the benefits of a single-use system. These include reduced utility requirements for steam-in-place and clean-in-place operations, faster turnover times between batches or products and reduced risk of cross-contamination. 

Operation at the 2000-L bioreactor scale also enables the implementation of single-use systems throughout the manufacturing process, most notably in media and buffer preparation and intermediate product mixing and hold steps, and in many cases, fully disposable chromatography, tangential flow filtration, and clarification and virus filtration operations. 

Even at the final filling stage, adoption of single-use technology is growing rapidly. The facility to operate these processes can be built, commissioned and qualified in 12 to 18 months at capital costs that are a fraction of a traditional facility. This allows companies to move aggressively into the biosimilars market at lower financial risk and, more importantly, allows for production of much needed medicines closer to the patient regardless of their location. This is the promise and the power of single-use systems. 



Michael Felo is group product manager, Single Use, at EMD Millipore. 

Articles

Single-use technologies, which started off as a tool for small-volume solution storage and transport has now become the central, enabling technology around which manufacturing processes and facilities are being designed.

Single-Use Systems: Enabling the Future of Biologics Manufacturing

Increased regulatory expectations and the need to mitigate risk have popularised the use of redundant filtration for bulk and final fill operations. Single-use redundant filtration (SURF) assemblies are an efficient and flexible alternative to stainless steel systems because they eliminate clean in place (CIP), sterilisation steps and the associated validation protocols. Preparation time can also be significantly reduced when using single-use assemblies because of their pre-sterilised format and the ease with which they can be handled. Redundant filtration operations in multi-product facilities can be performed without spending the extra validation time that is often required for non-disposable systems.

Credit to Ingram Publishing/the Agency Collection/Getty Images 

This article identifies a suitable design for redundant filtration operations using single-use technology and standardised assembly components. The design was finalised with input from a global technical and quality team with consideration given to international regulatory requirements. The article also demonstrates the capability of the assembly to withstand the high pressure that is used for integrity testing and drying. Pre-use integrity testing was performed on both filters. Using hydrophilic/hydrophobic filters on the assembly outlet eliminated flush volume limitations caused by catch bag size. Assembly specifications, such as leachables and extractables, hold up volume and flushing requirements, were established for a single-use assembly. 

As defined in PDA Technical Report 26, redundant filtration is a "type of serial filtration in which a second sterilising-grade filter is used as a backup in the event of an integrity failure of the primary sterilising filter." The pore size of the sterilising-grade filters may be the same or tighter than the primary filter (1). Other regulatory bodies (e.g., FDA, EMA and SFDA) have also issued their own guidelines for sterile filtration. According to the FDA's aseptic processing guidelines published in 2004, it is recommended that redundant filtration should be considered in many cases where liquid is sterilised by filtration (2). The EMA's 2008 GMP guidelines state that because of potential risks of sterilisation by filtration, a second filtration step as close to the filling point as possible is advisable (3). 

Designing a redundant filtration system that meets regulations and recommendations is challenging. For stainless steel systems, the EMA recommends that integrity testing should be performed on sterile filters before use. To do this, filters must be fully wetted without breaching the sterility on the downstream side of the assembly. Many conventional stainless steel facilities employ a "catch can" with a sterile vent filter to collect the initial flush liquid from the wetting step. Prior to use, additional time is required to sterilise, maintain and store the catch can. In addition, use of a catch can constrains the total flush volume that can be used if the filters need to be rewetted (e.g., in a repeated filter integrity test).  

Disposable or single-use redundant filtration (SURF) assemblies offer a flexible solution for this relatively complex operation (4). These assemblies can be presterilised by the supplier using gamma irradiation and there is no need for cleaning after use because assemblies are self-contained and entirely disposable.  

Proposed single-use process solution: design considerations

Many biopharmaceutical companies already use variations of SURF assemblies for final and bulk fill operations. However, preparation and utilisation sequences may differ across processes and geographies because of differing national guidelines.

 Figure 1: Utilisation sequence options for single-use redundant filtration assemblies. F1 is the first liquid filter. F2 is the second liquid filter. 

This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly that has greater operational robustness and minimises the risk of product contamination. Below are the major design considerations for the assembly (see 

A barrier filter (0.2 µm, EMD Millipore) was included in the design as a combined liquid and gas outlet. The barrier filter contains both hydrophilic and hydrophobic sterilising-grade PVDF membrane, which can exhaust both air and water from the assembly. As a result, it can be used as the initial filter flush outlet and as a sterile air outlet during integrity testing and the filter drying step. Such a filter further solves the problem of flush volume constraints imposed by the catch bag/tank size. The assembly can be wetted and tested for integrity multiple times without breaching the sterile envelope. 

Catch bags were attached to the vents of the liquid filters to collect liquid during venting. 

Gamma stable vent filters were attached to the bags to enable passage of air during venting. 

A hydrophobic PVDF filter was added on the air inlet line to ensure sterility of the air coming into the assembly for integrity testing. 

Single-use sterile connectors were used at the assembly's inlet and outlet to assure sterile connections during operation. 

In-line liquid filter capsules were selected (as opposed to T-line capsules) to reduce the hold-up volume. 

The assembly was used in the vertical orientation to achieve better draining after wetting and during product recovery after filtration.

The catch bag on the first liquid filter is primarily in place to avoid the liquid spill that can occur during venting for water flush and product filtration. With some minor modifications, the catch bags on both the first and second liquid filters can also be used for in-process sampling. The catch bag on first liquid filter and the separate air inlet line (with an air filter near the feed inlet) are additional features that are incorporated to ensure cleanliness and ease of operation.  

Pre-use, post-sterilisation integrity testing of a redundant filtration setup can be challenging. With either stainless steel or a singleuse assembly, it is critical to maintain setup sterility during every step. The efficiency of the filter wetting step is also important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. 

 outlines the utilisation sequence for SURF assembly before use. Along with the points mentioned above, operator convenience and regulatory compliance were also considered.  

A flushing test was conducted to record the reduction of total organic carbon (TOC) and conductivity with flush volume. The filters and assembly were flushed with deionised (DI) water at a flow rate of 250 mL/min for a total of 20 L. The assembly effluent was sampled at 1 L intervals and tested for conductivity and TOC. Analytical results for flush filtrate samples are summarised in 

. At the end of 20 L reverse osmosis (RO)/DI water flush, TOC and conductivity were 0.231 ppm and1.1 µS/cm, respectively. 

Figure 2: Total organic carbon (TOC) and conductivity (ÂµS/cm) versus flush volume (mL). 

Traditionally, the comparison of single-use versus stainless-steel processes is made on the basis of consumable cost versus capital cost, but other costs must also be taken into account to make an accurate comparison, including labour, validation and quality. Selection of the cost minimum option depends on the specifics of the application and accurate accounting of the associated costs of each technology. Labour rates and process costing assumptions are taken from Biosolve cost modelling software (Biopharm Software Solutions). 

 summarise the results of the cost analysis for a typical redundant filtration process using two 10 in. cartridges. The costs assumed here are representative of industry costs; it is assumed that difference in cost for utilities and materials (e.g., CIP solution, water for injection) does not significantly affect the cost comparison. The costs of pump and extractables–leachables validation are similar for both stainless steel and singleuse setup, so these costs were excluded from the analysis. 

Table I: Capital and validation cost. Capital and validation costs are taken over 10-year expected lifetime of the facility. 

SURF assemblies offer further benefits over stainless-steel setups. Equipment turnover for new products is quicker with single use assembly. For example, additional testing and cleaning time associated with equipment release and documentation is reduced or eliminated if singleuse technologies are used. It also provides more production flexibility because single-use assemblies can be made to order in the size and configuration required with the need for additional equipment or validation. It also eliminates the need to have multiple setups in place to meet the production demands of different products. 

Table II: Cost per batch. The cost calculations in this table are based on 12.5 h batch time for stainless steel setup and 6.5 h batch time for single-use assembly. The batch time is lower for single-use assembly due to elimination of preparation steps, cleaning procedure and ease of handling. 

This study identified a suitable design for redundant filtration operations by utilising single-use technology. An optimised utilisation sequence for preparatory steps was designed and tested. Conducting a pre-use integrity test on a pre-sterilised redundant filtration setup can be challenging, but an effective filter wetting step is important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. All preparatory steps and filtration operations can be successfully performed on a single-use assembly. SURF assemblies are robust and efficient disposable solutions for bulk and final fill processes. 

Journal of Pharmaceutical Science and Technology

Sterile Drug Products Produced By Aseptic Processing—Current Good Manufacturing Practices (Guidance for Industry)

"Guidelines to Good Manufacturing Practice—Manufacture of Sterile Medicinal Products," Annex 1

The authors describe a new assembly for bulk and final drug product filling operations.