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Validation and Testing Methods Used in Single-Use Technologies

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Bioprocessing

For pharmaceutical manufacturers it can be just as hard to keep up with demand as it is to keep up with the highly competitive market. Now you can do both with easy-to-use single-use connectors from CPC. They help maintain flow path sterility and integrity while enabling you to improve production yields, decrease time-to-market and reduce costs. Our genderless sterile connectors simplify process integration, maximize flexibility and streamline your supply chain efficiencies.

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Single-Use Technologies

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Steam-Thru® Connections

Single-Use Technologies: Steam-Thru

CPC’s patented Steam-Thru® Connection technology creates a sterile link between pre-sterilized bag systems or tube sets and stainless process equipment. The product’s innovative three-port design maximizes sterility assurance by eliminating “dead legs” and allowing steam to pass directly through the connection to “steam on” to stainless equipment.

Sterility assurance is further expanded with the introduction of CPC’s Steam-Thru II, which provides “steam on” and “steam off” capability, allowing both a sterile connection and sterile disconnection without the need for a laminar flow hood. This reduces the potential of microbial contamination of the process flow path, as well as environmental contamination within your facilities.

CPC’s Steam-Thru® product line includes several valve and termination options that give you the flexibility to meet today’s mounting and flow requirements. The connection is attached to single-use bag systems or tubing, then pre-sterilized by gamma irradiation up to 50 KiloGrays or autoclaved up to 129°C for 60 minutes, depending on the product configuration.

For mounting to the processing equipment, engineers may specify the connection with either a ¾” or 1-½” sanitary termination on the middle port. Tri-clover clamps are used to secure the middle sanitary to the equipment and the lower sanitary to the steam trap. Once attached, these two lower ports allow a true steam-through SIP process to eliminate potential “dead legs” that trap contaminants. With Steam-Thru® II, you can perform a SIP cycle of up to 135°C or 35 PSI for up to 60 minutes to “steam on” the connector to the equipment. Effectiveness of the “steam on” cycle was confirmed through bacterial challenge testing using Bacillus stearothermophilus performed at the University of Minnesota’s Biotechnology Research Center.

Once the SIP cycle is complete, the operator simply depresses the thumb latch to allow valve transition from the steam position to the flow position. This creates a sterile flow path between the stainless equipment and the single-use system, allowing aseptic fluid transfer. A benefit of the Steam-Thru® II valve design is a maximum Cv value of 8.2, which translates to a flow rate of 43.9 liters per minute at 2 PSI, making it appropriate for high volume applications.

After fluid transfer is complete, depressing the thumb latch again allows repositioning of the valve back to the steam position for a second SIP or “steam off” cycle. This eliminates any biologic residual remaining between the process equipment and the single-use system, minimizing the potential for environmental contamination at disconnection.

In addition to the bacterial challenge testing completed on the “steam on” cycle, bacterial challenge tests were performed following media transfer on the “steam off” cycle. Bacterial ingress tests using Brevendimonas diminuta were conducted by Northview Labs to verify post-sterilization seal performance. Other performance tests, including helium/steam leak, tensile and maximum burst were completed to assure design and process integrity. The Steam-Thru® II is comprised of non-animal origin USP Class VI polysulfone and platinum-cured silicone seals, which were tested for biocompatibility.

Single-Use Applications

Transfer Lines

Single-Use Transfer Lines: Overview

Biopharmaceutical manufacturers are constantly implementing new ways to leverage existing plant infrastructure to enhance process reliability and flexibility. One solution that continues to gain momentum is single-use systems—particularly single-use transfer lines—which can deliver significant value through added flexibility, improved asset or equipment utilization and lower costs.

Initially, single-use systems consisted of tubing, bags, filters and connectors. Bioprocessing facilities used these systems for process storage applications and sterile cell culture media. Single-use bioreactors then entered the market in research and development labs and rapidly moved into pilot plants and larger scale production facilities as integral systems for production and seed train scale-up. Now, single-use transfer lines are used throughout the bioprocess to reduce operational costs. Unlike hard piping, the flexible tubing in single-use transfer lines does not require expensive and time-consuming cleaning and validation.

Manufacturers can more efficiently manage business cycles by quickly changing process steps or converting to a new product—a key advantage for multiple product facilities in which process requirements change with the drug being produced.

Innovative manufacturers now incorporate single-use transfer lines in the following:

    • Seed Trains

   • Suite-to-Suite Transfer

   • Final Fill Applications

Single-Use Transfer Lines: Seed Train

You can use single-use transfer lines in conjunction with your existing processing equipment to reduce validation and maintenance costs with stainless steel piping and valves. For example, a 10,000 L production suite with stainless steel bioreactors can integrate single-use technology for cell culture media storage and key transfer lines.

• Single-use media storage systems arrive at the bioprocess facility sterilized by gamma irradiation and often fitted with integrated filters, sampling systems and connectors

• A single-use SIP connector allows operators to make sterile connections between these pre-sterilized single-use systems and stainless steel bioreactors for aseptic transfer of media

Similarly, operators can use single-use transfer lines to move inoculum between bioreactors, using either a peristaltic pump or headspace pressure.

• Such transfer lines can reduce the number of reusable valves required for transfer and can eliminate problem areas for CIP and SIP validation

• Terminating each pre-sterilized transfer line with a single-use SIP connector provides sterility assurance equal to that of traditional fixed piping at lower capital costs

Single-use systems are connected to a cell culture media storage bag—either by aseptic welding or with a CPC AseptiQuik® Connector—using flexible tubing. Likewise, flexible tubing with AseptiQuik® connections is used for transfer lines between each reactor in the process. For production volumes over 1,000 L, a single-use bioreactor must ultimately seed one or more stainless steel bioreactors. CPC Steam-Thru® Connections incorporated into the single-use bioreactor design can link the single-use and stainless steel section of a seed train.

For added safety, you can use an HFC39 quick disconnect coupling that has been validated as an aseptic disconnect to remove single-use bags and tubing after the media transfer is complete.

Single-Use Transfer Lines: Suite-to-Suite Transfer

Traditional bioprocessing facilities transfer medium from the production suite to a preparation suite by using stainless steel manifolds with piping or reusable hoses as transfer lines. Advances in single-use technology allow bioprocess engineers to replace most storage vessels and fixed piping networks with single-use storage systems and tubing assemblies. Single-use eliminates the need for CIP validation for many components and reduces maintenance and capital expense by eliminating expensive vessels, valves and sanitary piping assemblies.

Process engineers now incorporate single-use transfer lines between the bioreactor in the process suite and the transfer vessel. Using pre-sterilized connectors and tubing, the medium can be moved from the production suite to the preparation suite without the need to sterilize stainless steel piping or equipment. This enhanced mobility eliminates many of the restrictions that hard-plumbed piping can place on the manufacturing facility and allows the manufacturer greater flexibility when determining which process to run in each production suite.

Especially in multiproduct facilities, the risk of cross contamination in the suite-to-suite transfer process is high and can potentially lead to product loss or reduced production yields. Pre-sterilized, single-use assemblies reduce these risks and improve the speed and safety of drug development and delivery.

Single-Use Transfer Lines: Final Fill Operations

Traditionally, final fill operations included stainless steel equipment connected via reusable valves, rigid tubing and steel pipes. Today, many process engineers are designing this operation with single-use transfer lines instead of stainless steel equipment to reduce sterilization time and cost.

Final fill tanks are designed to transfer formulated product from formulation suites to storage areas and ultimately to filling suites. To allow sterile connection to and from these vessels, designers traditionally added three-way valve assemblies to fill and drain ports. Replacing these heavy assemblies with single-use transfer lines and connectors eliminates cleaning validation and maintenance, while reducing mobile vessel weight by tens of kilograms.

Sterility Assurance

Sterility Assurance: Overview

As biopharmaceutical manufacturers gain firsthand experience with the benefits of incorporating single-use systems into their facilities, they’re now expanding the use of these systems in both upstream and downstream applications. This is no surprise, as increased volume and diversity of pharmaceutical products is compelling manufacturers to design their facilities based on shorter production runs with multiple changeovers. Meeting these demands requires operational flexibility. Production facilities must be able to easily add new products, rapidly convert processes and quickly make operational adjustments as needed. This is where CPC’s single-use systems can deliver significant value: These systems offer many benefits, including rapid implementation and cost savings.

Innovative manufacturers now incorporate single-use transfer lines from CPC in the following:

    • Adapting Facilities for New Products

   • Creating a Completely Sterile TFF Loop

   • Steam-Thru® Technologies

Sterility Assurance: Adapting Facilities for New Products

Although many biomanufacturing facilities were designed around Clean-in-Place (CIP) or Steam-in-Place (SIP) equipment and fixed stainless steel piping, adapting these facilities for new processes reveals the significant advantages of single-use systems.

One major manufacturer implemented a new process that required flushing of a critical filter element prior to filtering their final drug formulation. This single-use, SIP filter is encased in a stainless steel housing that was not piped for a filter-flush step. Their solution was to design a single-use bag system with a CPC Steam-Thru® II Connection inlet to capture the flush solution. This bag system is received pre-sterilized and routed through their cGMP raw material inspection and release process.

When preparing the filter for SIP sterilization, the bag is connected via the Steam-Thru® II to the filter housing’s bleed port. During SIP, steam passes through the filter housing, out the bleed port, into the Steam-Thru® II middle port and out the lower port to a steam trap. Once SIP is complete, the Steam-Thru® II valve is transitioned to the flow position creating a sterile flow path for collecting the flush solution. After the filter flush is complete, the Steam-Thru® II valve is transitioned back to the steam position, which isolates the bag system and flush solution.

Sterility assurance is the primary reason the manufacturer selected a single-use bag system with the Steam-Thru® II as an inlet:

“When filtering during drug formulation steps, maintaining sterility is an absolute priority. The combination of pre-sterile bags and the Steam-Thru® II provides the assurance we need without additional process equipment.”

Another factor considered was Steam-Thru® Technology’s track record:

“We’ve used Steam-Thru Connections for several points upstream in other processes over the past few years, so when we identified this new problem downstream, we knew that Steam-Thru would meet our requirements.”

Integrating single-use components with traditional stainless steel processing equipment can help manufacturers increase flexibility and adapt facilities for new processes, while maintaining process and product sterility.

Sterility Assurance: Creating a Completely Sterile TFF Loop

A major biopharmaceutical manufacturer selected CPC’s Steam-Thru® Connections as part of their downstream tangential flow filtration (TFF) system out of concern for maintaining process sterility. Their specific technology consists of two-layer microspheres composed of biopolymers about the size of red blood cells. This size creates a serious problem for downstream processing: unlike therapeutic proteins, once the biospheres are assembled, they cannot undergo any sterile filtration steps at 0.1 to 0.2 μm. This required the downstream engineers to design a robustly sterile process system.

One critical purification step was microfiltration TFF. To meet their sterile assurance requirements, the manufacturer developed a sterile TFF loop consisting of both reusable stainless steel and single-use components. “Using Steam-Thru, we can connect our single-use waste collection bag in advance and sterilize the connection point when we SIP our stainless steel retentive vessel. After actuating the Steam-Thru valve, we’ve created a completely sterile TFF loop with both reusable and single-use components.”

Ease-of-use and storage issues are other benefits of the system:

“Steam-Thru Connections are lightweight compared with steamable valve assemblies. Our 200 L single-use bag system with the Steam-Thru doesn’t require much storage space allowing us to keep 1000 L or more of waste collection capacity on a couple of shelves. Cleaning one vessel instead of two for our TFF is also a big plus.”

Integrating single-use systems into the microfiltration TFF process can help manufacturers streamline process steps and reduce cleaning and validation, while providing the assurance of a completely sterile TFF loop.

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