The Development of Single-Use Aseptic Processing Systems
John Boehm, Bioprocessing Business Unit Manager, Colder Products Company

Though the connecting device or connection method may appear to be a small part of an overall system, connection and disconnection of tubing for process fluid transfer is a critical aspect of single-use processing, and manufacturers need to carefully consider the available options because the connector can be the deciding factor in keeping the single-use bioprocess truly aseptic.

Today’s high market demand for biologic and pharmaceutical products challenges bioprocessors to review their processing systems and seek ways to make them more flexible, reliable and cost effective, and as a result, more manufacturers are turning to single use manufacturing, which provides a number of advantages from lowering operating costs and reducing contamination risks, to improving production yields and increasing process flexibility.

Below is a list of benefits that single-use offers
  • Economic Advantage - reduces capital requirements for new facility builds or retrofits of existing facilities and smaller facility footprints are possible.
  • Safety/Quality - reduction of cross contamination risks and improvements in sterility assurance not only reduce product loss but make it easier to produce multiple products within a single facility .
  • Speed to Market - shorter facility builds and reduced validation cycles support the challenge of developing and introducing new therapies (critical in all segments but even more important in the race to develop biosimilars).
  • Operational Efficiencies - these include reduced cleaning requirements and labor costs, faster product changeover, and reduced downtime.
  • Operational Flexibility - the ability to run multiple drugs in the same facility or quickly convert for product or campaign changeover is possible.
  • Sustainability - less energy, chemicals and water are expended than traditional stainless systems.
Examples and case studies of single-use technology in use have also become more common. The aforementioned benefits have led to strong adoption of single-use manufacturing by major biopharmaceutical manufacturers throughout the United States and Europe for nearly 20 years;

adoption is also increasing throughout Asia. Here are some notable examples of companies basing their manufacturing on single-use:

Shire, for instance, has been quite successful in a business strategy that leverages a platform of specialty biopharmaceuticals that include a broad range of smaller revenue drug therapies. The flexibility of singleuse allows them to produce a wide range of products in flexible facilities based on single-use manufacturing. A noted highlight of their activities includes building and commissioning a new world-class facility in only two years, versus a traditional stainless facility which typically takes five years or more.

Catalent Pharma Solutions is an example of a contract manufacturer that requires the flexibility and sterility assurance to produce an ever -changing range of products for a variety of different clients. They continue to replace stainless-based processes with single-use processing equipment. They also took advantage of the speed of implementing single -use technology to retrofit an empty building into a multi-cleanroom facility in approximately one year.

In Singapore, Amgen is in the process of building and commissioning a new facility of the future based on single-use technologies.

There are many more examples of global drug manufacturers presently working on projects to implement closed modular system designs that drive increased volumes to lower costs and increase process flexibility while maintaining or increasing sterility assurance.

Increasing demands of single - use technologies mean that there needs to be robust supply that offers customers greater choice. There is a full range of different single-use connection technologies available, depending on the customer's applications and specific needs. Solutions range from basic quick connects and fittings to advanced steam-in-place (SIP) and sterile connectors. When the first single-use bags transitioned from the blood market into biopharmaceutical applications nearly 20 years ago, plastic quick connects and fittings were utilised to connect these early systems. These MPC and MPX connectors have become an industry standard and are still widely accepted throughout the industry to make aseptic connections under a laminar flow hood. The introduction of new additions to these product families including back -to-back adapters solve the issue of connecting two male connector halves or two female connector halves. These adapters can also easily connect systems with different tubing diameters.

With the evolution of single-use system design came the introduction of Steam-in-Place (SIP) connectors that allow a sterile connection to be easily and reliably made between stainless processing equipment and single-use bags and tubing assemblies. SIP connections are a critical tool to help drug manufacturers utilise existing stainless equipment while benefiting from the advantages of single-use through the creation of hybrid systems.

Further developments have created a range of sterile connect and disconnect technologies for tubing and related applications which are easy-to-use, robust sterile connections for applications from small flow 1/8" tubing for sampling bottles and cell culture bottles and trays to large flow 1" tubing applications. These include single-use bio reactors , mixers and disposable filling systems.

Nowadays a one-time sterile disconnect of pre-sterilized systems for applications like buffer preparation and filter integrity testing is also available. Besides, other offerings include a range of solutions that combine SIP, sterile connect and sterile disconnect combinations to further ease the configuration and integration of single-use systems.

With so many choices offered, there are a number of key factors to consider when choosing the correct connection solution;they include:
  • Ease of use - this is a critical factor in minimizing operator error and assuring repeatable and reliable performance.
  • Robustness - robustness is a must to assure product quality and customer confidence.
  • Process scale -appropriate solutions for the flow and pressure requirements of a particular application should be considered.
  • Material compatibility - meets sterilization and chemical compatibility along with appropriate extractable profiles.
  • Existing equipment - compatibility with existing processing equipment is especially important for hybrid systems that combine stainless and single-use processes.
  • Available solutions - customers need to be aware of the full range of solutions available.
  • Past validation work/validation materials - potential time savings achieved by using validation work previously completed by a global validation team or another corporate facility should be considered.
  • Vendor reputation - the manufacturer's expertise in connection technology to provide the required technical support is an important factor.
After the solution has been chosen and installed, there are several strategies to support customer validation, including utilizing vendor validation testing data for product performance and extractable, etc. Many customers are working to validate products once for global approval across all their facilities, which are often supported with technical support from the vendor including FMEA evaluations. Users can also reference BioProcess System Alliance (BPSA) Quality Test Matrices for single-use connectors to gain valuable technical references over best practice component tests.

To conclude, connection technology has certainly advanced in recent years and continued innovation is expected. This will enable the growth of aseptic processing by providing the ease of use, reliability and sterility assurance required by connections in support of advanced single-use systems.