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Updates to USP <665> Standard and <1665> Guidance for Single-Use Technology Users

September 24, 2020

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In part two of this three-part blog series we look at the September 1, 2020 updates to the United States Pharmacopeia (USP) <665> standard and <1665> guidance for single-use technology (SUT) users.

 

Whether applied in hybrid formats aligned with traditional stainless-steel technologies or taking a more modern approach in fully single-use systems (SUS), SUTs offer users an enhanced level of flexibility and reliability for the life of their bioprocess. Still, because SUT have various components (filters, biocontainers, bags, sterile connectors, tubing, etc.) that are in contact with ingredients or end products throughout the process, qualification of extractables and leachables (E&L) in those components is important. Because E&L can make their way into a process from heat or solvent exposure, or can migrate over time with continued contact, proper qualification and preparation is necessary to protect the process, and ultimately, the patients. 

 

In part one, Advances in Single-Use Technology Standardization, we explored the BioPhorum end-user best practices guide for evaluating leachables risk from polymeric SUS with comprehensive supplier extractables data for single-use disposables. Now we take time to review the September 1, 2020 updates from the United States Pharmacopeia (USP)—a non-profit 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)—and do an initial comparison to the BioPhorum guidance. 

 

An Overview of the Updates 

 

The updated drafts of the USP <665> standard and <1665> guidance chapters of the Pharmacopoeia Forum cover plastic components and systems used to manufacture pharmaceutical drug products and biopharmaceutical drug substances and products. 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 USP <1665>. 

 

The publication of the latest USP <665> and <1665> (available in links at the end of the blog) chapters represents a major step forward to finalizing the compendial requirements for what data should be provided by suppliers to support evaluation and qualification of fluid-contact process equipment used in biomanufacturing. The risk-based approach helps suppliers prioritize the right level of data for the vast array of different components marketed today.  

 

A Couple of USP <665> Clarifications

 

Historically, suppliers and end-users have considered USP <88> or Class VI plastics testing as a requirement for all fluid contact materials. However, the USP <87> and <88> are not fully suitable to today’s bioprocesses. 

 

One Class VI compliance requirement includes animal implantation testing, which is now facing increased scrutiny, particularly since bioprocess plastics are not implanted in humans. Many have argued that USP <87>, which avoids animal testing, should be the sole requirement, but this conflicts with a large amount of the relevant USP <88> data. And since most plastics are designed to meet Class VI requirements, the full relevance of the standard is in question. 

 

In today’s age of mass spectrometry and strong chemical analytics, some regulators have suggested compliances such as USP <87> and <88> carry little to no value in an application review. Given this lack of consensus, USP <665> completely avoids the topic of USP <87> and <88>. 

 

And when it comes to USP <661>, which historically was served as a baseline test for plastic resins, components and container closures, this has been withdrawn and now redrafted with a specific emphasis on container closures and the resins with which they are made (i.e. USP <661.1>).) Earlier drafts of the USP <665> proposed standard, including that from March 1, 2019, placed strong emphasis on qualifying plastic resins per USP <661.1> and <665>, making it more complicated for users. 

 

In the latest draft, it is clearly stated that the new USP <665> standard completely satisfies the USP physicochemical requirements alone.  

 

Qualification vs. Selection

 

In the March 1, 2019 draft of USP <665>, there was contentious debate as to whether USP <665> was required for component qualification and selection. While qualification covers compliant suitability for use, selection is ultimately an end-user decision involving costing, business risk, usability, and other intangible attributes.  

 

The latest USP <665> incorporated feedback from regulators clearly stating that the primary goal of <665> is to standardize requirements enabling component qualification for a large majority of typical applications. As USP <665> sets the requirements for a baseline qualification, it is recognized that a small fraction of applications may require additional data or justification. 

 

A Cursory Comparison

 

The 2014 and 2020 BioPhorum protocols are focused on simplifying the risk assessment approach for single-use components used in biomanufacturing. 

 

The scope of USP <665> is more broadly encompassing to include all plastic components—single-use or multi-use—for traditional, small molecule (with exception of active pharmaceutical ingredients (APIs)), or biologics manufacturing. 

 

Overall, the extractables testing prescribed by the USP <665> compendial requirement and the BioPhorum end-user best practices are similar and should both be used to facilitate component qualification. The latest USP <665> shows considerable attention and strong alignment with the May 2020 BioPhorum guidance, with the same categories and descriptions used for components, and testing timepoints which are a subset of those prescribed by BioPhorum. Still, when the USP updates are aligned with BioPhorum best practices, additional testing may be required to further simply the end-user risk assessment process or help to differentiate supplier components in a highly competitive market. 

 

Standard Value

 

Ultimately, both guidance documents offer tangible and complementary value to end users and suppliers alike. 

 

At Pall Biotech, we actively stay up to date on regulatory updates from USP and align with BioPhorum to ensure that we are focusing resources where they will benefit users most. Our goal is to build value into our SUS for the life of every process. 

 

Visit us here again soon to read the final Part Three of this blog series, where we look at a few critical differences in the guidance documents, and how that impacts end users and suppliers. 

 

If you want to learn even more on the USP updates, access the on-demand webinar I participated in with Ken Wong, Deputy Director from Sanofi-Pasteur and Desmond G. Hunt, Principal Liaison at USP on the September 1 launch date. 

 

Click to view USP <665> Chapter, “Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products” 

 

Click to view USP <1665> Chapter, “Characterization of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products

 

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James Hathcock, PhD, Senior Director, Regulatory and Validation Strategy

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 phorum as well a USP <665> expert panel member.
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 phorum as well a USP <665> expert panel member.
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