Updates and Comparisons of USP <665> and <1665> Chapters and the 2020 Biophorum Guidance

In part three of this blog series we compare the September 1, 2020 updates to the United States Pharmacopeia (USP) <665> standard and <1665> guidance and the May 2020 updates to the BioPhorum best practices guide for extractables testing of single-use components.

In the past decade, single-use technologies (SUT) have become an accepted and common part of successful bioprocesses. But even as these technologies have gained traction and advanced over time, it remains imperative for users to understand that materials from components like filters, biocontainers, bags, sterile connectors, tubing, etc. present the possibility of leachables entering the process.

Single-use systems (SUS) must be properly qualified for E&L risk, and standardization remains a hot topic across the industry. Standards bodies and advocacy groups continue to work to ensure that end users and suppliers have more guidance on developing and implementing these enabling technologies.

A Tale of Two Guidance Documents

BioPhorum launched in 2009 as an industry advocacy group to accelerate standardization via end-user guidance. In May 2020, the BioPhorum best practices guide for extractables testing of single-use components was released, with comprehensive supplier extractables requirements for single-use disposables. Reviewed in 2020 Advances in Single-Use Technology Standardization, the updates built on the original 2014 BioPhorum protocols.

The United States Pharmacopeia (USP) is 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). On September 1, 2020 updates were made to the proposed USP <665> standard and <1665> guidance, which we covered in Updates to USP <665> Standard and <1665>.

Digging into the Differences 

While the summary of component categories, solvents and timepoints in the USP <665> are generally aligned with the BioPhorum guidance, there are some differences, including:

Risk-Based Testing Requirements: Where the BioPhorum guidance is largely a ‘one size fits all’ risk testing protocol, the USP features three levels of testing depending on the expected level of component risk: low, medium, or high risk. 

Silicone and Elastomeric Materials: BioPhorum guidance generally applies to all fluid-contact polymeric materials in single-use bioprocess components, including elastomeric materials.

Although silicone and elastomeric materials are generally amenable to the characterization testing prescribed by USP <665>, they are not directly within scope of the chapter on ‘plastic’ components. USP has historically considered elastomers in the context of those used for injectables in USP chapter <381> and is conscious to avoid conflicting chapters on the same materials. It is expected USP will focus on developing guidance for silicone components in its 2020-2025 cycle.  

Solvent Selection: The original BioPhorum approach to solvent selection focused on worst case solvents used by most biomanufacturers, whereas the USP took the approach to select a minimum portfolio of scientifically justified solvents to cover at least 80% of typical bioprocess applications. Consequently, the BioPhorum low and high pH solvents encompassed a broader range (pH ~1.6 to ~13.5), as compared to those prescribed by USP <665> (pH 3 to 10). In addition, BioPhorum includes additional timepoints that are expected to bracket short and long exposure times. USP focused the single time-point relevant to most applications. 

Further variation in criteria were established to align with the BioPhorum guidance, including: 

• Organic extract: 50% ethanol is expected to simulate or exaggerate the organic properties of most biopharmaceutical fluids and is common to USP and BioPhorum guidance. 50% ethanol profiles typically contain the greatest number of extractables from either protocol or is the single solvent required for USP <665> medium risk components. 

Moreover, the 2020 BioPhorum best practice guidance has included a new category for small components that requires only the 50% ethanol/water profile.  

• Low pH extract: USP standardizes pH 3 as a reasonable worst-case acid solvent representing most acidic bioprocess fluids, but allows for substitution with the Biophorum recommended 0.1 M phosphoric acid (~pH 1.6) solvent. The rationale for the substitution came from data shared as part of a USP workshop that indicated both pH 1.6 and pH 3 yield similar extraction profiles1,2.

• High pH extract: For the high pH solvent, USP continues to standardize on pH 10 as a reasonable typical worst-case pH, whereas BioPhorum continues to require a 0.5 N NaOH (~pH 13.5) solvent. USP does allow for the use of 0.5 N NaOH, but only for cases where the drug manufacturing process fluid exceeds pH 10, meaning that in most cases, a pH 10 solvent profile will be expected for high-risk components. The rationale for the USP pH 10 requirements was that:
  1. pH 10 would cover most pharmaceutical applications where the process fluid could lead to leachables that persist in the process stream 
  2. Limited data suggested that 0.5N NaOH (pH ~13.5) may lead to considerably different or worse profiles than pH 10
  3. A standard requirement for pH compatibility at pH ~13.5 could disadvantage innovative new plastics that would be perfectly suited for most pharmaceutical applications at pH less than or equal to 10

For component manufacturers adopting the full BioPhorum protocol, expect to see 0.5 N NaOH (~pH 13.5) datasets in addition to the pH 10.  

• Water: Water extraction profiles are not a requirement for USP <665> but continue to be a requirement per BioPhorum. USP, in effort to identify the minimum solvent portfolio that covers the broadest range of applications, argues polar extractables compounds are adequately profiled through extraction of a low and high pH extraction solution, and that an additional requirement for a polar extractables profile in relatively neutral water would be largely redundant. BioPhorum, in contrast, conducted a limited-scope review of chromatographic peak data shared by suppliers in 2019, and were unable to reach a conclusion that water profiles were redundant, so this remains a user-requirement specification for BioPhorum.  

Regardless of the compendial and BioPhorum user requirements, it is understood that water is a highly relevant solvent to many pharmaceutical applications, and often contains fewer compounds to risk assess than a composite of low and high pH profiles. Hence many suppliers, such as Pall, will provide water extractables profiles for high value components to simplify component risk assessment and qualification.   

• Other Solvents and Time-Points: A 2019 review by BioPhorum end users of supplier provided data lead to a recommendation to remove 1% polysorbate 80 and 5 M NaCl from the 2020 BioPhorum best practice requirements. In addition, the requirement for a less than 30-minute extraction profile was also deemed to provide minimal value to the overall risk assessment and was also removed.  

Achieving Bioprocess Success

For every bioprocess, end-users own the responsibility to ensure they have adequate data to support a product quality and patient safety risk assessment. Standardized expectations, such as those from USP <665> and BioPhorum, help streamline and accelerate the E&L risk assessment process, allowing focus on more pressing needs. Continued end user and supplier engagement is critical to assessing and providing the right-level of data (USP low-, medium-, high-risk or full BioPhorum protocol) for the right application.

Working with a supplier like Pall that is actively engaged in following USP standards and aligning with industry advocacy groups like BioPhorum can offer another layer of protection and ease when making these serious decisions. Our team innovates and documents all our SUS, SUT and components to make qualification and selection simpler and safer and offers optional complementary service support for process development and acceleration. You can trust that our team will be there for the life of your process, without fail.

Read more about <USP 665> in the Biotech Regulatory SME Corner. 

Still interested in learning more? Check out our on-demand webinar with Ken Wong, Deputy Director from Sanofi-Pasteur and Desmond G. Hunt, Principal Liaison at USP.

References

¹ Tumambac, Song, Xing, Li, Lu, Liu, Shih, and Hathcock.  Implementation of the BPOG extractables Testing Protocols: Working with Multiple Single-Use Components. Bioprocess international. Dec 2017.

² Tumambac, Song, Li, Li, Shih and Hathcock.  Implementation of the BPOG extractables Testing Protocols:  Comparing USP and BPOG Extractables Data for Autoclaves Polyethersulfone Filters. Bioprocess International, Jan 2018.