Single-use or disposable biomanufacturing replaces stainless steel tanks, bioreactors, and plumbing with plastic, to provide flexibility, agility, and speed to the production of therapeutic proteins. A recent market study estimates demand for for Single Use Upstream Processing to grow at up to 15% per year through 2021, when demand will reach $3.7 billion..

As disposable processing worked its way from less critical steps (e.g. media and buffer storage) to more critical unit operations (cell culture, filtration), extractables and leachables (E&L) became a cause of concern. Leachables are chemicals that migrate from the single-use container into the process solution during normal use. Extractables, a subset of leachables, are found when single-use equipment undergoes heating or contact with solvents.

Just as consumers are concerned about chemicals from plastic packaging entering their food, biomanufacturers worry about the effects of E&L on patient health. E&Ls may interact unfavorably with, or even neutralize, biopharmaceuticals, thus rendering medicines ineffective. Moreover, the toxicology of plasticizers, slip agents, surface enhancers, monomers, and initiators normally found in plastics opens up a closet of unknown, potential health effects.

E&Ls affect the health of cultured cells as well. A study by Amgen scientists confirming that a common anti-oxidant additive to plastics inhibits cell growth is just one of many such investigations. For a fanatically risk-averse industry like biotech cell toxicity, the potential for human toxicology, and the prospect of falling out of compliance suffice to warrant action.

As the the senior expert on E&L at Nelson Laboratories, Matthew Jorgenson, Ph.D., oversees the design of E&L studies in a dynamic regulatory and competitive environment. Nelson Labs also educates manufacturers and interacts with regulators on the science and regulation of E&Ls.

Nelson explains that over the last several years E&L testing has become significantly more complex and sophisticated. “Five years ago, an extractables study involving measurement of dried residuals by FTIR only was considered acceptable. Today, methods once common only to pharmaceutical work have been streamlined and applied more universally to medical devices and single-use biomanufacturing devices.” Today, extractables studies involve the use of multiple solvents plus analysis for metals, volatile organics, semi-volatile organics, and non-volatile organics using chromatography and mass-spectroscopy.

“The application of chemistry, vs. biological, data to make determinations regarding the use of devices and patient safety is relatively new. In vivo and in vitro biological tests, for example modified Eagles medium (MEM) elution for cytotoxicity, and chromosomal aberration for genotoxicity, have traditionally dominated the evaluation.”

Manufacturers and regulators now accept that chemistry tests provide more detailed and better-predictive data for systemic toxicological effects of E&Ls than biological testing. The evolution of these tests has been rapid as the adoption of single-use bioprocessing continues.

Single-use bioprocessing equipment uses biocompatible plastics as materials of construction. , which have a history of safe use and regulatory acceptance via the medical device industry. Adapting these materials to single-use bioprocessing has proved to be more problematic than anticipated, and plastics manufacturers are unlikely to invent new materials specifically for bioprocessing any time soon.

“Biocompatible plastics represent a tiny sliver of the overall plastics market, diminishing the motivation for raw material suppliers to accommodate the stricter standards of end material with reduced E&Ls,” Jorgenson says. Instead, suppliers have focused on reducing E&Ls by employing higher-purity homopolymers (plastics consisting of a single subunit). “Part of the shift to low E&L-releasing plastics has been the increased use of chemistry testing in material evaluation and the upcoming enforcement of regulations requiring the use of CMR-freematerials.”

In this climate, where E&Ls will remain an accepted risk in single-use bioprocessing for the forseeable future, the object is to characterize, understand, and control the implications of E&Ls rather than to eliminate them. Major stakeholders are therefore focusing efforts there, and on developing appropriate regulatory standards.

At the same time the regulatory landscape is changing rapidly. The recently released ISO 10993-1standard, for example, shifts the focus towards evaluation of single-use plastics using a risk-based approach to evaluating biocompatibility. “And the ISO 10993-18 standard, on ‘chemical characterization of materials,’ which is in the final revision stages, will dramatically update the current acceptable approaches to E&L,” Jorgenson says. “There has been a lot of movement and feedback from the FDA regarding what they expect from these studies. Just within the last six months, our perception of what regulators expect in terms of E&L has changed quite significantly.”

 

Special thanks to Angelo DePalma, PhD for his contributions to this article.

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