Single-use technologies (SUT) enable flexibility and reliability across the life of a biopharmaceutical process. Though these technologies have existed since the end of the nineties, strong uptake of SUTs for bioprocessing did not start happening until 2009 to 2010. Despite the potential, a change-averse industry mentality made most companies hesitant to become early adopters.
Just a decade later in 2020, this aversion no longer remains and there has been uptake across the industry. A broad spectrum of SUT solutions can be integrated as a hybrid with traditional stainless-steel technologies through to fully single-use systems (SUS) for upstream, downstream, and fill/finish applications. All these systems require various components (filters, biocontainers, sterile connectors, tubing, etc.) that are in contact with ingredients/drug products throughout development and manufacturing. This makes it critical to have a standardized approach to impurities risk assessment for SUS to easily aggregate and risk assess data and avoid lost batches, or worse, harm to patients.
Progress in standardization with BioPhorum
Various advocacy groups and companies actively align with global regulatory guidance to interpret and monitor standards. BioPhorum was launched in 2009 to accelerate innovation via end-user guidance.
In 2014, BioPhorum published a defined extractables protocol that was intended to provide robust and standardized extractables characterization of SUT components, and thereby minimize overall industry testing cost and accelerate the qualification of SUS. By the end of 2017, however, it was recognized that the data were:
- Difficult to obtain and compare due to study design and reporting formats
- Scattered in quality because of challenges with LC/MS identification, solvents issues, and contract lab quality
- Limited in availability, because suppliers were not actively participating, either due to cost and complexity, or because they preferred to wait for updates to the United States Pharmacopeia (USP) <665> protocols
This realization in late 2017 led BioPhorum to invite suppliers into the BioPhorum extractables and leachables (E&L) workstream. The goal of the joint biomanufacturer-supplier activity was to find solutions that achieved the original ambition of simplifying SUS qualification in a way that works for both suppliers and end users. Via bi-weekly collaborative discussions and three face-to-face meetings, the workstream published a long-awaited updated version of the BioPhorum best practices with supplier extractables data incorporated in May 2020 with strong participation from both biomanufacturers and suppliers, the updated best practice guidance is expected to greatly improve the availability, quality, and usability of the data.
What is in the 2020 BioPhorum protocol?
In the revised 2020 Best Practices Guide for Extractables, a core focus was placed on expanding the guide from scientific testing protocols into an ecosystem that enables easy access and application of high-quality supplier data. In terms of the technical requirements for the protocol, the BioPhorum team agreed that any substantial changes or omissions from the original 2014 protocols required a 70% vote from end-users. Supporting the rationale for any changes, a small, highly dedicated end-user team conducted a technical review by biomanufacturers of more than 28 different extractables datasets from 6 types of single-use components provided by 7 different suppliers (of which 7 datasets were supplied by us). The conclusion of the data review team indicated that specific solvents and timepoints yielded little unique information and would not significantly contribute to the risk assessment. Based on the recommendations of the data review team, the BioPhorum biomanufacturers in the workstream successfully voted on a number of key changes that significantly reduced the overall level of required testing.
Some of these major updates include:
- Removal of 5 N NaCl and 1% polysorbate 80 solvents
- Removal of initial (< 30 min) timepoint
- Removal of elemental analysis for 50% ethanol solvent
- A new component category for small parts, which requires only the 50% ethanol solvent profile
- Peak reporting threshold changed from > 50% higher than control to 300% of control, thereby reducing compounds suspected to noise in the data
In addition to the updated technical specifications, there is a drive to create an ecosystem that makes it easier to find, understand, and use the supplier datasets via:
- Data sharing rules for how reports are expected to be passed from component manufacturers to integrators, to end-users without complex multiway confidentiality agreements or disclosure of sensitive customer information
- Specific structures and requirements for extractables reports, including downloadable spreadsheet templates required for reporting the summary data
- Component family templates defining how testing of a single component part number may be used to bracket similar components within the same family
- Assembly family templates detailing how to document the different components within a single-use assembly
- An online extractables portal with links to supplier web pages, where a structured list of available extractables reports can be found
- An ongoing community of practice composed of 71 individuals from 17 biomanufacturers and 13 single-use suppliers
- An online frequently asked questions (FAQs) resource that is kept current to address additional challenges with implementation of the protocol
What’s coming next in standards?
The United States Pharmacopeia (USP) is a nonprofit organization that sets public standards for drug manufacturing and drug products that are recognized and enforced by the United States Food and Drug Administration (FDA). BioPhorum best practices and user requirement specifications (URS) always take USP and global regulatory body guidelines into consideration, with the aim of creating complementary protocols and resources.
On September 1, 2020, the USP will publish an updated draft of the USP <665> standard and <1665> guidance chapter in the Pharmacopoeia Forum. Both USP publications will detail standardized supplier extractables requirements for single-use components resulting from 4 years of engagement between end-users, suppliers, and regulators. An aligned USP compendial standard and BioPhorum URS will clarify the type of data a component manufacturer is expected to provide for filters, biocontainers, connectors, tubing, etc., and enable a simplified approach to implementing quality by design (QbD) and quality risk management (QRM) best practices for qualifying single-use systems in biomanufacturing.
Learn more in parts 2 and 3 of this blog series:
Part 2: Updates to USP <665> standard and <1665> guidance for single-use technology users
Part 3: Updates and Comparisons of USP <665> and <1665> Chapters and the 2020 Biophorum Guidance
Author bio
James Hathcock is responsible for extractables and leachables (E&L) characterization strategy to support the safe and successful end-user implementation of technologies enabling pharmaceutical manufacturing. He is an active member of ASTM, ASME-BPE, PDA, ISPE, BPSA, Biophorum-supplier forum as well a USP <665> expert panel member.