Colder's John Boehm Discusses Important Considerations For Biopharm Manufacturing

Single-use systems are gaining greater acceptance in biopharmaceutical manufacturing as companies increase the diversity of products they manufacture and redesign processes based on shorter, multi-product runs. Manufacturers who are incorporating single-use systems into their processes realize the added benefits in validation cycle time and cost savings, improved contamination control capabilities and higher yields. We recently talked with John Boehm of Colder Products Company to learn more about the increasingly important role single-use systems are playing in biopharmaceutical manufacturing.

Q: What are some of the reasons manufacturers are incorporating single-use systems into production processes
A: Single-use, or disposable systems, are being used to replace many types of expensive, stainless steel bioprocessing equipment such as filter housings, hold tanks and transfer lines, with disposable filters, bioprocessing bags and tubing sets. Single-use systems offer many benefits over stainless steel equipment, including faster implementation, reduced validation requirements, cost savings and lower capital investment. Finally, single-use product can improve overall production yields as part of a manufacturer’s integrated contamination control strategy.

Q: Are there specific types of contamination that bioprocessors need to control in their production processes
A: Yes. There are three potential sources of common contamination: cross contamination, microbial contamination and biologic contamination of the process facility. Each contamination type can be addressed through the use of single-use systems.

Q: What is cross contamination and what are the potential risks
A: The potential for cross contamination occurs when process equipment is used to produce more than one protein. Unwanted protein contamination may reduce production yields by requiring additional purification steps, or in the worst possible case, proteins that co-purify may result in potentially fatal treatments.

Q: How do manufacturers using stainless steel processing equipment prevent cross contamination
A: To prevent cross contamination in stainless steel processing equipment, bioprocess engineers must develop and validate clean-in-place (CIP) procedures that remove all residual proteins between processes. These CIP cycles typically use large quantities of caustics, acids and water-for-injection (WFI) and require regular testing to verify effectiveness. Making simple equipment changes such as adding a new valve may require partial or complete CIP revalidation, increasing time and labor costs.

Q: Can single-use systems be used to effectively prevent cross contamination
A: Absolutely. Single-use systems can reduce or eliminate the need for CIP by starting with virgin polymers that meet USP Class VI biocompatibility and extractables requirements. Single-use component and systems manufacturers typically make and assemble products in clean rooms to ensure their products do not introduce harmful particulates and endotoxins into a bioprocess. Because tubing, connectors, bags and filters are used only once, proteins from other processes cannot be introduced.

Q: What about the threat of microbial contaminations
A: Microbial contamination is one of the greatest threats to bioprocesses. Once microbes – such as bacteria, yeast and fungi – enter the nutrient-rich bioprocess environment, they quickly overwhelm mammalian cell cultures, utilizing all available nutrients and secreting unwanted and harmful proteins or endotoxins. A bacterial contamination can destroy product valued at millions of dollars in a matter of hours.

Q: What do bioprocessors do to prevent bacterial contamination
A: Manufacturers dedicate enormous resources to developing a sterile bioprocess environment and maintaining aseptic conditions during production and purification. Sterility can be achieved via heat, irradiation or chemical agents. Bioprocess equipment is primarily sterilized by heat in the form of pressurized steam: autoclaves are used for small-scale equipment and steam-in-place (SIP) processes are used for medium- and large-scale systems. As with CIP, SIP processes must be validated to insure sterility.

Q: How are single-use systems sterilized
A: Certain single-use systems may be sterilized by autoclaving; however, most are sterilized after assembly by irradiation, from cobalt 60 gamma source or e-beam, or using ethylene oxide (EtO) gas as a chemical sterilant.

Q: How can process engineers incorporate pre-sterilized single-use systems to prevent bacterial contamination
A: A variety of techniques are used to aseptically connect pre-sterile, single-use systems together or to process equipment. Integrated single-use filters may be used at the point of connection to create sterile additions. With quick connectors, such as luer fittings or couplings, aseptic connections can be made in Class 100 laminar flow hoods using proper aseptic techniques. For connections in an open or Class 10,000 process environment, tubing welders and aseptic connecting devices, such as the Kleenpak™ Connector and BioQuate DAC allow single-use to single-use connection. SIP connectors like the Steam-Thru® Connection effectively control microbial contamination while allowing an aseptic flow path to be created between single-use systems and stainless steel. These systems are pre-sterilized prior to being introduced into the process.

Q: Outside of the bioprocess environment, are there other areas for potential contamination
A: Definitely. Maintaining a clean process facility can be as critical as maintaining an aseptic bioprocess environment.

Q: What are the potential risks of biologic contamination in a facility
A: Biologic contaminations within process facilities increase the risk of microbial contaminations within bioreactors and other process equipment. Additionally, biologic contamination may pose a health risk for bioprocess technicians, especially in viral vaccine manufacturing facilities.

Q: What practices and procedures are used to prevent biologic contamination
A: Bioprocess technicians employ a number of systems to maintain cleanliness in Class 10,000 areas. These include clean room gowning, regular contamination monitoring and cleaning, rigorous pass-through procedures and specialized cleaning methods following facility maintenance or suspected contamination.

Q: Can single-use technologies be used to prevent biologic contamination in a facility
A: Single-use systems provide an excellent means of preventing external contamination from entering a bioprocess facility when they incorporate components capable of making both a sterile connection and a sterile disconnection. This is an ideal application for the use of single-use SIP connectors that allow a second SIP cycle to make a sterile disconnection in order to minimize suite contamination when removing the single-use system from process equipment.

Q: What are some of the potential benefits manufacturers will see by incorporating single-use systems
A: Single-use systems offer manufacturers reduced validation time and cost, and help to increase production yields. They also serve as an integral part of reducing or eliminating the threat of contamination that can cause serious health risks to bioprocess technicians.

Q: Are there limitations to incorporating single-use systems as a means to prevent biologic contamination
A: Single-use systems can be deployed to address specific contamination concerns in existing processes by integrating appropriate disposable technologies along with traditional stainless equipment. In certain cases these concerns are best addressed by a redesign or a complete single-use system. These approaches are not limited to upstream or downstream processes, new or existing facilities; the benefits of advanced contamination control can be realized throughout the manufacturing operation.

About John Boehm, Bioprocessing Business Unit Manager
John Boehm is responsible for Colder Products Company’s bioprocessing business unit. John joined Colder Products Company in 2001 and has held various positions in engineering, marketing and business development. John has a B.S. in mechanical engineering and an MBA. John is the chair of the BioProcess System Alliance (BPSA) education committee.