April 15, 2014 (Vol. 34, No. 8)

Vendors Work to Standardize Protocols but Resist End Users’ Calls for Interoperability

Intellectual property issues and lifecycle-level business decisions seriously limit inter-vendor interoperability for single-use bioprocessing equipment. Nevertheless, standards are evolving through the collaboration between vendor and end-user working groups. Within a few years we can expect consensus on issues related to materials of construction for films, tubing, and connectors, and on validation testing for extractables, leachables, and particles.

For now, true interoperability—using one vendor’s tubing with another’s connector, for example—is asking too much of an industry that is constantly evolving and barely 15  years old. Even mature industries struggle with interoperability. Think of how automobile companies employ different parts from year to year, and even within one model-year.

Every provider of single-use equipment expects their proprietary connector technology to provide a revenue stream for the duration of its patented life, says Eric Isberg, a member of the Bio-Process Systems Alliance (BPSA) and global product manager, Integrity™ single-use fluid technologies at Pall Life Sciences. (Isberg’s former company, Bloomington, Minnesota-based ATMI, was acquired by Pall in February 2014.)

“There’s quite a bit of competing interest as to which technology, whether it’s a standard or sterile connector, should become the standard,” Isberg notes. The same holds for tubing and film. Vendors expect to be able to sell their own proprietary components as part of single-use systems.

The BPSA works closely with its end-user counterpart, the decade-old Biophorum Operations Group (BPOG). The BPOG formulates specifications from an end-user’s perspective. For example, it consolidates biomanufacturers’ views on leachables and extractables. In general, it develops specifications on the basis of its member companies’ collective assessment of their regulatory challenges and safety needs.

In concert with the BPOG, the BPSA then implements an iterative process to arrive at functionality standards that appeal to both sides.

The first standards to emerge from this collaboration will affect intrinsic material properties. Interoperability is not even on their radar screen. Given the state of flux and innovation in single-use processing, the low priority accorded interoperability is understandable. Also, single-use suppliers play down interoperability because customers already enjoy “catalogs of choices,” according to Isberg.

Still, one might ask why, with more than a decade of experience with single-use systems in critical manufacturing operations, the two “BPs” have yet to agree on specific test standards for quantifying leachables, extractables, and particles.

“We’re close,” Isberg observes, “but there is a history there.”

During the rise of disposable processing, each single-use supplier conducted its own independent studies on material-related impurities. Those tests, as could be expected, served the vendors’ own needs with respect to films and anticipated usage. Protocols differed in terms of materials, methods, and time points. As much larger suppliers absorbed smaller, innovative single-use suppliers, they assumed those legacy test methods as well. To mix metaphors horribly: vendors explain the current situation as “more than one way to skin a cat,” while users tend to view it as so many apples-to-oranges comparisons.

The BPOG has released recommendations on which chemicals should be used to induce leachables/extractables, as well as exposure times, temperatures, and other conditions. Now the ball is in the BPSA’s court.

“We will assess what we’ve already done and see how we can fill the gaps to meet end users’ recommendations,” Isberg remarks. “The BPSA has been responsive, and it has already gone back to the BPOG with recommendations.” A similar process is under way for particulate testing. Users enjoyed an official advance view of the BPSA’s ideas at Interphex 2014, where they had the opportunity to provide feedback.

Not the Way Things Work

Paul Priebe, director for fluid management technologies at Sartorius Stedim North America, echoes Isberg’s sentiments. “Standardization is being discussed in several forums, but it’s not about the technology—fittings and connectors, for example—or the basic way things work. The state of innovation in the single-use space makes standardizing technologies premature. If you look within bioprocessing in general, standardization never occurs until IP expires.”

He gives as an example the tri-clamp, a kind of stainless-steel sanitary fitting that at one time consisted principally of a branded and patented design from a single company. Once the patents expired, competitors began copying the design, and eventually, through efforts of ASME’s BioProcess Equipment group, the design became standardized. “But the process took many years,” Priebe admits.

A similar situation exists today regarding the leading aseptic connector, Pall’s KleenPak™. Suppliers today provide work-arounds that provide similar (some would claim identical or superior) function.

Tri-clamp and KleenPak illustrate how areas of standardization that users fret most about are those where innovation is occurring, and where patent protection assures that the status quo will persist for years.

“Users are understandably frustrated,” Priebe explains. “They want this stuff to be easy. But each connector has its place in a vendor’s offerings and in bioprocessing. Each comes with its own value proposition. And to decide which one should become the standard, well, we’re just not ready for that. Expecting the leader to award open licenses, so anyone can copy its design, is unrealistic.”

As with the biopharmaceutical industry at large, developers of innovative single-use equipment factor lifetime revenue streams, based on solid IP protection, into their strategic planning. Differentiation, value, and profits are the keys to generating profits that lead to next-generation innovation. Standardization, Priebe argues, results in commoditization, which stifles innovation.

“The right places to focus standardization are with issues that all industry suppliers, and their customers, face. That is why the BPOG and the BPSA work on those areas, and not technology and interoperability.” This is reflected, Priebe says, in the fact that the BPOG initiative furthest along involves extractables protocols. “When these standards eventually emerge, users will understand them, know how to read them, and be assured that the information they contain is useful.”

The parallels between value-seeking activities in single-use equipment and biomanufacturing are striking. Intellectual property fuels innovation in both, which is why companies in these parallel industries fight commoditization tooth and nail, if sometimes to the detriment of end-users or patients.

For now, bioprocessors must be satisfied that cooperative competition between the BPSA and the BPOG is leading, albeit slowly, to standardization in several areas that directly affect patient safety.

A production operator performs an in situ pre-use leak test on a single-use bioreactor with the Sartocheck 4 plus Bag tester, part of a family of products provided by Sartorius Stedim Biotech.