Regulatory Expectations and Consensus Industry Recommendations for Extractables Testing of Single-Use Process Equipment - BPSA eases confusion over extractables and leachables testing through guides

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Regulatory Expectations and Consensus Industry Recommendations for Extractables Testing of Single-Use Process Equipment
BPSA eases confusion over extractables and leachables testing through guides.


BioPharm International Supplements


BPSA Introduces Updated Extractables Guide

Recognizing the need for further education on extractables testing, including extraction and analytical methods, BPSA began to develop a follow-up guide providing more extensive information on methods of extraction and extractables analysis in 2009. The resulting BPSA 2010 Extractables Guide white paper, "Recommendations for Testing and Evaluation of Extractables from Single-Use Process Equipment"6 was developed by an expert team representing suppliers, users, and independent testing laboratories.

The 2010 BPSA Extractables Guide begins with a review of the key concepts introduced BPSA's 2008 white paper, then expands on the previously proposed risk-based approach, providing recommendations for extraction conditions, explanations of analytical methods, and suggestions for users on how best to evaluate and compare supplier-generated data.

The first section covers three revisions made to the 2008 extractables white paper.
  • Two levels of risk evaluation are now differentiated—the first, for materials, includes information on polymer chemical compatibility, generic extractables data, and suitability for use. The second risk evaluation considers drug product-related toxicity and quality risk, evaluating the extractables data as presumptive leachables by calculating worst-case levels in downstream process fluids and final drug product, and applying recognized toxicological assessment methods.
  • A change was made to the decision tree flow chart originally published in the 2008 white paper, which included an option to test only for leachables in intermediates or final products in the absence of adequate supplier extractables data. Subsequent discussions with CBER reviewers highlighted the need to more strongly address concerns that leachables could be masked in protein solutions. BPSA recognized that to analyze for potential leachables in biopharmaceuticals, knowing the extractables from process equipment was not an option. In the 2010 BPSA Extractables Guide, the option to skip extractables testing if unavailable and go directly to leachables testing is omitted.
  • The third revision in the 2010 BPSA Extractables Guide is the introduction of the term, migrants, to refer to potential leachables from process equipment. Several end users have noted that in FDA and EMA documents, the term leachables only appears in reference to final product containers and packaging, not to process equipment, and looked to BPSA to recognize this distinction. In response, BPSA has introduced the term migrants when referring to chemicals that leach from process equipment, but may or may not be detected as "leachables" in final product dosage containers.

A revised risk decision tree highlights materials risk evaluation, which incorporates a review of available generic extractables data and determining sufficiency, followed by application of that data to the drug product and performing a risk evaluation for toxicity and product quality. After the risk assessments are done, a decision can be made whether the available extractables data, when considered as potential migrants, are sufficient, or whether further testing for migrants from the process equipment into the actual process fluid, where they may be detected as leachables, is merited. In the latter case, both data on extractables and migrant (i.e., process-derived leachables) should be submitted in regulatory filings.

The next section of the 2010 BPSA Extractables Guide provides detailed considerations on extraction conditions, including selection and preconditioning of test articles such as autoclaving, irradiation, and flushing. BPSA recommends water and ethanol as primary worst-case solvents representing most bioprocess fluids, and also discusses options for other extraction fluids. Model extraction conditions are differentiated by component types and summarized in a detailed table covering filter capsules, tubing, sterile connectors and fittings, biocontainers, mixing bags, and bioreactors.

This is followed by an extensive section on analytical methods, including detailed descriptions of applicable techniques—what they do, what they detect, and what their limits of detection are. This section on "what you need to know about analytical methods" is intended to guide suppliers in generating appropriate data, and enable users of single-use systems to better understand suitable extractables data and the implications to their process and product.

Lastly, the guide provides recommendations for user actions when extractables data from suppliers are incomplete or inadequate. Suggestions also are provided for comparing data from different suppliers of comparable components where extractions may have been conducted under differing pretreatment or extraction conditions or different analytical methods.

Availability of supplier-generated core (generic) extractables data generated according to consensus recommendations, as proposed by BPSA, can minimize duplicate testing by users for individual and multiple drug products. These conditions and analytical methods are intended to guide suppliers and users to develop more comparable extractables data that facilitate user and regulatory evaluations. Copies of the 2010 BPSA Extractables Guide can be purchased from BPSA at http://www.bpsalliance.org/.

Jerold Martin is the senior vice president of global scientifi c affairs at Pall Life Sciences, Port Washington, NY, 516.801.9086,
He also is the chairman of the Board and Technology Committee at Bio-Process Systems Alliance.

References

1. BPSA Extractables and Leachables Subcommittee. Recommendations for extractables and leachables testing of single-use–part 1: Introduction, regulatory issues, and risk assessment. BioProcess Int. 2007 Dec;5(11):36–49.

2. BPSA Extractables and Leachables Subcommittee. Recommendations for extractables and leachables testing of single-use–Part 2: executing a program. BioProcess Int. 2008;6(1):44–53. BPSA. Available from: http://www.bpsalliance.org/.

3. FDA 483 response review memo. Available from: http://www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm161014.htm.

4. FDA 483 response review memo. Available from: http://www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm161016.htm.

5. Sillivan, DM. Review of single use processes and materials: overview of types of data to be reviewed and specific areas of concern. IBC's 7th International Single Use Applications for Biopharmaceutical Manufacturing, La Jolla, CA: 2010 Jun 14.

6. BPSA Extractables Subcommittee. Recommendations for testing and evaluation of extractables from single-use process equipment. 2010: Washington, DC. Available from: http://www.bpsalliance.org/.


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