With the escalating use of single-use technology in bioprocessing, suppliers have had to rapidly develop disposable components such as fittings, tubing, pumps, sensors, and flexible containers for bioprocessing. Single-use technology is growing so fast that the organizations tasked with guiding its growth are having difficulty keeping up. Contributing to this problem are factors such as company needs, regulatory requirements, market pressures, and costs.
That growth has posed considerable concerns for the bioprocessing industry about the presence of organic and inorganic particles within formulations, leachables, the hygienic integrity of connector unions, and control of single-use system component changes. As single-use technology advances, many bioprocessing experts realize that these areas require improvement, especially in detection and control of particles. The industry understands the potential expense and danger to products and patients that particle contaminants can cause and the resulting need to move to a higher level of product quality and patient safety. To reach that, components and processes require a higher level of standardization.
The pharmaceutical industry realizes that no one group could solve all bioprocessing challenges, particularly in single-use applications. Hence, multiple groups are coordinating to address standards development. This collaboration has increased significantly over the past year. The BioPhorum Operations Group (BPOG), a group that involves some of the largest pharmaceutical companies, is driving much of this movement.
Leading the charge is the American Society of Mechanical Engineers, Bioprocess Equipment Group (ASME-BPE). Resulting from widespread industry requests for standardization, ASME-BPE is a unique group. While focusing on operational standards relating to patient and product safety, it incorporates current best-practices in designing and building equipment and systems for producing pure and safe products. This is one of only a few organizations that can write standards, and it publishes them biennially. The current ASME-BPE standard was published in 2014, and the group is now working on its 2016 standard.
Other groups are also actively involved in this process. The BioProcess Systems Alliance (BPSA) was formed in 2005 as an industry-led corporate member trade association dedicated to encouraging and accelerating the adoption of single-use manufacturing technologies for production of biopharmaceuticals and vaccines. The American Society for Testing and Materials (ASTM) focuses on testing standards. The European Deutsches Institut für Normung (DIN) and Japanese Pharmacopoeia also take part in the development of ASME-BPE standards.
Until the past few years, those organizations worked independently to resolve issues relating to bioprocessing. Because of the commingling of membership between all the organizations, many members are encouraging them to work together. Representatives from different organizations now meet regularly to exchange information. And all participant groups recognize ASME-BPE’s dedication to consistency in standards.
Jay Ankers, chairman of the ASME-Bioprocess Equipment Group, says that the organization created a standard around the design of bioprocessing equipment so that manufacturers could design such systems better and make safe drug products for patients. “It was at that time that we aligned with BPSA and began working together. Over the past two years, additional groups started working closely together to cover what each was responsible for instead of everybody going after the same thing.”
Ankers adds that BPE “has the largest group of subject matter experts under one roof that consistently publishes a book every two years.” That voluntary consensus standard follows ANSI-accredited guidelines. We communicate with the European DIN, Japanese Pharmacopoeia, and Chinese and Canadian regulatory agencies. Everything is checked by the subcommittees, the standards committee, and then the ASME board to make sure that correct procedures are followed. Then it goes out for public review.” Ankers says that regulatory agencies such as the US Food and Drug Administration (FDA) like to see such processes use and reference the set of consensus standards that have been required by law since 1995. “That is why BPSA and BPOG recognize BPE and hold us in high regard.”
One serious complaint from pharmaceutical manufacturers is that connections, tubing, bags, and mixers are made by different manufacturers so that frequently such components do not fit together well enough and cause leaks. Drug makers have asked ASME-BPE to develop manufacturing standards that will help these components fit together flawlessly and perform as expected. Standardization would relate to physical parameters such as dimensions and tolerances relevant to process design. In standardizing the form, fit, and function of individual components, uniformity in container–connection technology and systems would ensure better connectivity among disparate operations.
With stimulus and support from BPSA, ASME-BPE has focused on standardization of dimensions and tolerances for single-use components such as tubing and connections, within particular unit operations. ASME-BPE’s Polymeric Hygienic Unions task group has taken the lead on this issue, which is currently in debate and working through the BPE standards process. A section of the 2014 document included some standardized dimensions. Machining and data collection are under way to help the group determine what sizes work or fail. Hose-barb standardization is another key factor being addressed. Aside from the obvious benefit of providing consistently secure and safe hygienic connections through maintained structural firmness, standardization would provide biomanufacturers with the ability to keep a large inventory of single-use components, reduction of lead time between ordering and shipping, and the option to purchase uniform products from multiple suppliers.
A new ASME-BPE task group focusing on integrity of single-use systems has been established, primarily addressing leak testing. But the desirable properties of films, tubing, and solid plastic components also would need standardizing, as would testing methods for measuring those properties. Conferences with this task group’s members are ongoing. Eventually, a pressure test will need to be developed to validate hygienic unions. The ASME-BPE task group would look to ASTM to write that portion of the standard.
ASTM has produced a guide on specifications, designs, and verification of single-use manufacturing systems and equipment (1). The document is intended for use by suppliers, subsuppliers, and end users of disposables. It takes into consideration the unique traits of single-use components and their use in the biopharmaceutical industry. BPOG continues to offer consensus support to ASTM in the development of such design-verification standards.
Patient safety and risk management remain critical focus areas for regulatory agencies such as the FDA. Their requirements are becoming increasingly stringent. Tightening standards and regulations are pushing bioprocessors and suppliers to improve operating procedures and comply with such guidelines. Drug manufacturers say that the products they use need to be held to the same standards. So FDA requirements become the starting point for discussion.
Particles can come from many different sources in manufacturing environments: tools and equipment, workers, and components such as gaskets and seals, vials and syringes, and tubing, fittings, and bags. ASME-BPE’s 2014 standard contains several items specific to this subject (2). Guidance for manufacturers and end users of bioprocessing equipment will help them develop and manufacture products and systems that meet particle acceptance criteria. Those would include standardized hygienic-union dimensions, steam-through connections, and product–process contact as it relates to system boundaries and facility design.
At BPSA’s 2014 International Single-Use Summit, the group issued a particulate white paper (3) that was developed by subject matter experts from both bioprocess suppliers and end-users. This document not only helps to characterize and quantify types and levels of particles in single-use systems and components, but it also recommends procedures for minimizing those types and levels. BPSA has formed a task group to develop methods to detect particles in the single-use technology fluid path.
A new section is ready for the ASME-BPE 2016 standard on mitigation techniques (as well as controls) that suppliers and end users can put into place to minimize particulate matter. The standard also includes a small amount of content in its nonmandatory section on characterization, with a few references for acceptance criteria. The task group is currently anticipating ASTM’s work in this area before finishing that section. The group has aligned its efforts with BPSA, BPOG, and ASTM to develop this section of the standard together.
Improving the quality of bioprocessing to generate the fewest particles will simultaneously satisfy the goals of end users, suppliers, and regulators while ultimately protecting the safety of patients.
Movement on Change-Notifications Standard
Manufacturers of single-use bioprocessing components occasionally need to make changes to products that they sell to the biopharmaceutical industry: e.g., regulatory changes, tube and connector resin changes, dimensional changes prompted by design improvements, and other necessary modifications. If a biomanufacturer has spent six to 24 months validating a particular product in its own process, including obtaining all necessary FDA approvals, then that company certainly does not want supplied components for that process to change. The FDA, however, does recognize that occasionally changes must be made.
Situations that would require change notices (and associated time frames) are currently a hot topic of debate going through the ASME-BPE standards process. For the second time, the group has balloted a proposal on change notifications to its Standards Committee for incorporation into the next ASME-BPE standard. It would focus on change control for polymeric materials in disposable components. The ballot already has been approved at the subcommittee level and gone to the main committee, representing a significant start on a necessary topic. The proposal lists examples of significant changes that require notification and makes a recommendation of six months notification for planned changes.
BPOG and BPSA also are involved in developing that section of the standard. Both share the same position about the need to standardize supplier change notifications. The organizations have formed a task group to define levels of change, provide a streamlined standardized template for change notification, and facilitate an implementation process. A meeting of the two groups in spring 2015 promoted further communication and cooperation in working together toward this common goal.
ASME-BPE, BPOG, and BPSA members consider change notifications to be a measure of significant importance. Continuing to build on this section will be a priority at upcoming ASME-BPE meetings, where more discussions on change notifications will take place.
Focus on Standards
Demands for smaller batch sizes, greater process flexibility, and reduced manufacturing costs have driven the acceptance of single-use systems in the bioprocessing industry. Disposable components offer significant advantages over traditional multiuse parts and technologies. But this shift to single-use systems requires standardization.
“From the drug manufacturers to the device manufacturers, to the stainless steel equipment manufacturers, they all realize the need to invest in these standards,” says Ankers. “Otherwise a government agency will fill that void by defining how we need to operate.”
1 ASTM WK46541: New Guide for Specification, Design, and Verification of Single-Use Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. American Society for Testing and Materials: West Conshohocken, PA, 2014; www.astm.org/database.cart/workitems/WK46541.htm.
2 Appendix N. BPE-2014: Bioprocessing Equipment. American Society of Mechanical Engineers: New York, NY, 2014.
3 Recommendations for Control, Testing and Evaluation of Particulates Within Single-Use Process Equipment. Bio-Process Systems Alliance: Washington, DC, 2014.; www.bpsalliance.org/technical-guides.
Ken Davis is the global marketing manager of Nordson Medical at 805 West 71st Street, Loveland, CO 80538; 1-970-267-5200, www.nordsonmedical.com.