Pharmaceuticals: Regulatory Affairs

Progress in single-use technology standardization for bioprocessing

By James Hathcock, PhD, Senior Director of The Regulatory and Validation Consulting Team, Pall Corporation

Fully single-use systems and single-use technologies offer unmatched bioprocessing turnaround times and flexibility, with drastic reductions in cleaning requirements, cross-contamination risks, and cost. However, it is vital to ensure that the various components that contact ingredients and drug products throughout product development and the manufacturing process are properly characterised for extractables and leachables risk in order to avoid negative impacts on the process.


ioprocessing equipment has evolved over the past two decades so that nowadays, instead of all process work being done in traditional stainless steel or glass systems, many bioprocesses employ single-use technologies (SUT). Whether implemented along with traditional technologies in hybrid formats, or employed in standalone mode, fully single-use systems and single- use technologies (SUTs) offer unmatched turnaround times and flexibility with drastic reductions in cleaning requirements, cross- contamination risks, and cost. While SUTs offer many benefits, there are various components (filters, biocontainers, sterile connectors, bags, tubing, etc.) that contact ingredients and drug products throughout development and manufacturing and these components must be properly characterized for extractables and leachables risk to avoid negative impacts on the process. This has historically been done via costly and time-consuming testing methods. The cost and complexity can be so great that it has often been cited as the number one barrier to adoption of SUT[1]

. Making a change

Over the past decade, the industry has come together in agreement that standards will benefit end users, suppliers and most importantly, patients. When it comes to SUTs, the goal has been to align efforts from industry advocacy groups and regulators to


extractables characterization of SUT components[2]

. Unfortunately,

in 2017, it was recognized that adoption was lacking, and that even when data were generated, they were difficult to obtain and compare because of variations in study design and reporting formats.

By James Hathcock, PhD, Senior Director of The Regulatory and Validation Consulting Team, Pall Corporation

create standardized extractables data on fluid-contact single-use components and systems to eliminate redundant testing. The approach is similar to that seen in other industries (hi-tech, aviation, etc.) where the collation and documentation of reliable baseline datasets and expectations helps to save time and money while placing the focus back on innovation. True progress has been made, and carried forward, in 2020, with recent updates to SUT extractables protocols from BioPhorum and the United States Pharmacopeia (USP)<665> chapter. The following offers an overview and comparison of the recent updates.

Industry best practices

The BioPhorum is an advocacy group that launched in 2009 to accelerate innovation via end-user guidance and in 2014 it published an ambitious extractables protocol intended as a robust solution to standardizing

Quality was also a challenge due to immature LC/MS identification libraries, method development issues with the solvents, and challenges assessing and working with external contract labs. Still, active participation was the greatest barrier, as many suppliers were putting off the time and cost investment while waiting for updates to the existing USP <665> standard[3]


To remedy these challenges, in 2017 BioPhorum invited suppliers into an extractable and leachable (E&L) workstream to find collaborative solutions for simplifying single-use system (SUS) qualifications that were mutually beneficial for suppliers and end users. Three subsequent face-to- face meetings were aligned with bi-weekly virtual discussions, and in May 2020, a new ‘Best Practices Guide for Extractables Testing of Polymeric Single-Use Components Using Biopharmaceutical Manufacturing’[4]

an updated guidance on supplier extractables requirements. The 2020 guide was written with input from about 17 biomanufacturers and 13 single- use suppliers, including the team at Pall Biotech. The 2020

The BioPhorum is an advocacy group that launched in 2009 to accelerate innovation via end- user guidance and in 2014 it published an ambitious extractables protocol intended as a robust solution to standardizing extractables characterisation of SUT components

different component datasets as they risk assess complex, multicomponent single-use systems.

Suppliers or contract laboratories can easily create a quality-signed PDF of the BEDS template and share the key summary data with end users in a spreadsheet format. FAQs regarding implementation of the BioPhorum protocol can also be found on the website.

The evolution of USP <665>

The USP is a non-profit organization that sets public standards for drug manufacturing and drug products that are recognized and enforced by the US FDA. On September 1, 2020, the USP published a fourth, and expected final, draft of chapters <665> and <1665> in the Pharmacopoeia Forum to cover plastic components and systems used to manufacture pharmaceutical drug products and

biopharmaceutical drug substances and products. The risk-based approach helps suppliers prioritize the right level of data to support qualification of fluid-contact process equipment.

As with all USP chapters, the low level (<1000) USP <665> chapter serves as an enforceable requirement, whereas the higher level (>1000) chapter provides substantial guidance on risk assessment approaches and how to implement <665>[7]


Industry standardization using baseline quality requirements for single-use technologies is aimed at simplifying expectations for SUT materials and driving a Quality by Design (QbD) approach to SUS design and risk assessment. Implementing a common language and expectation for key stakeholders, including regulators, end users, integrators, component manufacturers, and material

Pharmaceuticals: Regulatory Affairs

suppliers helps save time and cost, which are critical to enabling more innovation. And with minimised risks from unexpected compounds, product quality goes up.

USP <665> vs BioPhorum guidance

Both the updated USP <665> chapter and BioPhorum best practice guidance have placed considerable effort in aligning protocols to avoid conflict. However, some differences still exist. The BioPhorum protocols are designed to simplify the risk assessment approach for only single-use components used in biomanufacturing whereasthe USP <665> chapter includes all plastic components – single-use or multi-use – for traditional, small- molecule (with the exception of APIs), or biologics manufacturing. And while the BioPhorum best practices are largely a ‘one-size-

fits-all’ testing protocol, the USP features three levels of testing depending on the expected level of component risk: low, medium, or high risk.

Other notable differences include: Selection vs Qualification Selection is an end-user decision that involves a multitude of considerations including price, risk profile, usability, and experience/ preferences. Qualification, on the other hand, has to do with justification and suitability for use. Following publication of the March 1, 2019 draft of USP <665>[3]

, there was contentious

debate as to whether USP <665> was required for component selection or qualification. The latest 2020 USP <665> incorporated feedback from regulators and now includes language, specifically on qualification, to recognize that in

recommendations build on the aspirations of the original 2014 BioPhorum extractables protocol[5][2] with a review of 28 different single- use supplier datasets.

was introduced as

The BioPhorum E&L website[6] features easy access to the updated protocol, data reporting templates, guidance documents, and an extractables portal, which contains links to supplier extractables information. The downloadable BioPhorum extractables data summary (BEDS) template can be used to capture and summarize all key information required for the extractables report to make it easy for end users to compile and aggregate multiple

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