February 15, 2015 (Vol. 35, No. 4)

Fast-Developing Disposables Are Passing Through an Awkward

Despite its growing popularity, single-use bioprocessing is not an unadulterated joy. It is spotted with process quality concerns.

There are still limitations with single-use technologies,” remarks Berthold Boedeker, Ph.D., chief scientist, global biologics development, Bayer Pharma, “particularly in the areas of pretesting and the quality of disposables, standardization and qualification of bags and connections, and validation of leachables and extractables, as well as dependency on individual solutions from different vendors.”

To be fair, these limitations have not prevented single-use processing from achieving success after success. The successes, rather, are what make the limitations stand out.

Dr. Boedeker attributes the growing popularity of single-use bioprocessing to rising protein titers, particularly for monoclonal antibodies, which have led to smaller cell culture processes. Most cell culture processes—even many of the large-scale processes—are within the reach of completely disposable systems, which have an upper volume limit of 2,000 L.

As single-use bioprocessing applications proliferate, increasingly diverse stakeholders have occasion to contemplate the interactions between single-use materials and process fluids. These interactions have been the subject of numerous publications and conference tracks. They have also attracted the notice of an alphabet soup of committees and organizations representing the biopharmaceutical industry and its suppliers.

All these stakeholders hope to reach consensus on actionable events and standardization of studies. Consensus, however, is elusive because the risks of prolonged, intimate contact between single-use materials and process fluids is unclear. Even when they are armed with study data, the stakeholders find that risk prediction is an uncertain science.

One of the keys to success in the use of disposable technologies is to fully understand the impact on risk assessment of polymeric components such as those found in Cynergy® single-use tubing. [Entegris]

Managing Change

“Single-use bioprocessing is somewhat behind the container and closure market in terms of having developed consensus as to the correct extractables studies to implement,” asserts Jeffrey Carter, Ph.D., strategic projects leader for GE Healthcare Life Sciences. “The further you get from container-closure systems, the further away we are from accurately predicting these interactions.”

Even when suppliers understand the relevant factors—raw materials, potential extractables, and process fluids—they have difficulty predicting the complex interactions that might unfold over time. Suppliers must be in a position to demonstrate that associated risks remain stable over time.

“Although it is necessary to thoroughly characterize the raw materials, it is not sufficient,” explains Dr. Carter. “This speaks to change management. With single-use equipment, one has to be aware that change is inevitable. Without excellence in change management, raw material characterization packages run the risk of obsolescence.”

Regulatory restraints are purposely vague. The FDA does not mandate specific tests or extractables limits, only that manufacturing equipment should not adulterate the product. In that regard, the same requirements hold for all materials of construction, including glass and stainless steel.

The potential exists for biomanufacturers to find themselves at the mercy of suppliers regarding leachables and extractables. This potential, however, is unlikely to be realized in today’s business climate.

“In a purely transactional relationship, you will receive notification according to supplier policy, and only after a lot of the planning for the change has occurred,” Dr. Carter says. Customers, however, often invest in developing relationships with their key suppliers. Such customers, Dr. Carter indicates, can “benefit from early offline communication of a pipeline change, influence how the supplier qualifies the change, and [develop] more intimate understanding of the change.” These activites can help customers in subsequent risk assessments.

A key issue is change control management—how much information a supplier is ethically required to divulge, and when. Too much information can be as unhelpful as too little, as each notification can trigger action on the part of the customer. It comes down to definitions. “What is a change? Dr. Carter asks. “What is a notifiable change? What depth of information does the recipient of the change notification need or want to receive?

These questions are currently the subject of constructive discussion, for example, through the BioPhorum Operations Group. The industry will be well served to reach an understanding of how suppliers and end users should manage supplier change.

GE Healthcare Life Sciences’ ReadyToProcess single-use platform for biomanufacturing.

Standards Evolution

“When it comes to standards specific to single use, we need more clarity on what is being referred to,” says Jerold Martin, senior vice president, global scientific affairs, Pall Life Sciences. He is also chairman-emeritus of BPSA.

Martin explains that there are first official Standards (large “S”), which are internationally recognized voluntary consensus documents meeting specific requirements. Examples include Standards from the ANSI, AAMI, ISO, ASTM, ASME-BPE, and USP.

In contrast, there are standards (small “s”), which are generally regarded as best practices but have not been formalized by recognized consensus bodies. Examples include white papers, technical reports, and best practice guides (from individuals, ad hoc groups, or organizations such as the PDA, ISPE, BPSA, and PQRI) as well as guidance documents from regulatory agencies. These generally are “standardized” approaches proposed by subject matter experts that provide recommended preferences, but have not been codified by recognized industry consensus Standards organizations.

“It is important to recognize that unless a government body applies a “Standard” as a code or regulation, all Standards—large “S” or small “s”—are voluntary,” Martin insists. “Their value is derived by their broad agreement among all stakeholders.”

Single-use components are offered by multiple suppliers in multiple formats. While user demand has been the primary driver of increased choice, some users see a benefit to having fewer choices. This, Martin explains, can reduce both the burden of choosing a preferred supplier and the effort involved in qualifying alternate sources.

“There is also the idea that limiting choices may increase the likelihood of regulatory acceptance,” Martin notes. “The challenge, however, is that multiple formats exist due to a combination of intellectual property and user preferences, so there is as yet little agreement on what the limited choices should be.”

Another concept of Standards relates to making qualification of single-use equipment more prescriptive, in order to ease decision making, especially if qualification data can be provided by suppliers and reduce user qualification burden. The challenge here is the nagging uncertainty over regulatory expectations, and the healthy debate over what constitutes good science or essential data for component qualification.

Standards, Martin points out, develop according to two basic timelines. The first is when suppliers agree to adopt a nonproprietary design or methodology, often with limited user input.

Oft-cited examples are the USB computer connector and the VCS/Betamax formats for videotapes. This works fine as long as users are not consulted, or they agree in advance to limit themselves to a single option, and suppliers respond by choosing nonproprietary options or agree to license or purchase royalties on intellectual property rather than develop their own proprietary approaches. Because of demand from users for alternatives and choices, single-use technologies have evolved through multiple proprietary technologies.

The second way standards develop is over the long term, as an industry or application matures and ultimate agreements become possible. This was the case with tri-clamp-style sanitary flange connectors in biopharma. Before the 1990s, suppliers marketed numerous sanitary fitting designs and multiple variants of the tri-clamp flange fitting.  The tri-clamp-style Standard emerged only after decades had passed, and only with the benefit of user agreement and an absence of intellectual property restrictions.
“Extended periods of time are often required for subject matter experts to come to agreement,” Martin observes.

An example of an existing, applicable standard is the BPSA Component Quality Test Matrices, an excellent resource. It consolidates information from published reference documents that have been applied by suppliers to single-use components and systems. Originally published in 2007, an updated and expanded version is planned by the BPSA for 2015.

Current efforts to expand Standards (and standards) for single-use technologies are underway through the ASME-BPE, ASTM, USP, BPOG, PQRI, and other groups. Many of these will be published within a year or two. Voluntary implementation will likely take one to two additional years.

From All Directions

The FDA regulations require only that bioprocessors understand the impact of materials of construction on drug products—a classic example of pharmaceutical risk management, states Mike Johnson, global bioprocess applications manager, Entegris. Mitgating process risk means assessing what can go wrong, including leaks and bag failures. Even stainless steel equipment is not immune from concerns of ions leaching into process fluids.

“But the big concern is extractables,” Johnson advises. “Drug manufacturers are very much in tune with this idea, and they have been pushing back on suppliers to identify compounds that might enter the process.” Compounds of one sort or another, he adds, inevitably do.

Why has agreement on extractables and leachables taken so long? Johnson likens the process thus far to “natural evolution.” During the migration of bioprocesses from fixed-tank to plastic bioreactor, suppliers were free to employ materials of construction known to be safe by some objective standard. Processes varied significantly on the user side as well with respect to unit operation temperatures, durations, agitation, and process fluids.

“Each supplier had their own extraction fluids, times, and temperatures, but end users specified their own parameters,” Johnson says. “It became difficult to compare one material to another.”

Another factor that complicates comparisons is the fact that many single-use systems have components from multiple suppliers: tubing from one, connectors from another, bags from a third. Standardization with respect to materials does not yet exist, and it may in fact be impossible. “Nobody in this industry produces every component,” observes Chris Shields, global marketing manager, single use pharmaceutical products, Saint-Gobain Performance Plastics.

Saint-Gobain has a web-based rapid prototyping service enabling customers to construct components of a custom system, which the company then renders using a 3D printer. Even here, however, as Shields notes, finished systems employ parts from multiple suppliers.

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