The demand for single-use bioprocess systems in biotech and pharmaceutical manufacturing has expanded significantly over the
past few years. Applications for single-use systems in biomanufacturing range from upstream media preparation single-use bioreactors,
buffer preparation, and intermediate processing, to storage of active pharmaceutical ingredients (APIs), bulk formulations,
and filling of final dosage containers. Despite their increased acceptance and implementation, a primary concern with single-use
disposable polymeric equipment continues to be that of extractables and leachables. In contrast with final dosage container
and closure systems, the absence of specific regulatory guidance for process equipment extractables and leachables has many
drug manufacturers unsure of what data must be submitted.
In response to the interest in single-use disposable manufacturing and to address the challenges of associated problems affecting
the industry, the Bio-Process Systems Alliance (BPSA), the single-use biomanufacturing trade association, has developed best
practice educational guides on a range of topics including component quality tests, disposal issues, irradiation and sterilization,
the economics of single-use technology, and extractables and leachables. These guides tie together the expertise and leadership
of BPSA's supplier and end-user member companies to provide recommendations for industry best practices.
In December 2007 and January 2008, BPSA published its first white papers on extractables and leachables testing of single-use
process equipment.1,2 This was the first independent consensus guide that provided basic concepts of extractables and leachables from single-use
equipment, summarized the existing regulatory requirements, and recommended a risk-based approach that could reduce the amount
of testing required by users. As part of this initiative, BPSA also conducted a training seminar in February 2008, at the
headquarters of the FDA and CBER near Washington, DC, where we differentiated single-use process equipment from final dosage
container and closures, discussed the BPSA recommendations for extractables and leachables testing of single-use equipment,
and the proposed risk-based approach. BPSA also has encouraged its supplier member companies to develop more generic and comparable
extractables data that would reduce the burden on users for redundant testing.
Regulatory Expectations for Extractables and Leachables Data
In the ensuing period, BPSA has gotten positive feedback from users and regulators about the risk-based approach. However,
FDA 483 observations and warning letters continued to cite insufficiencies in extractables data submitted by biopharmaceutical
manufacturers in drug product applications.
For example, in an April 2008 prelicensing inspection 483, the FDA stated, "Besides the 0.22 Ám sterilizing filters, there was no leachable and extractable testing performed for the equipment and (--redacted--)
materials used in (--redacted--) purification process including purification of (--redacted--)."
The drug manufacturer submitted a validation project plan defining requirements for the evaluation of extractables and potential
leachables from the product contact components of the process equipment, filters, and chromatography media used to manufacture
(the) drug substances and products, and the risk assessment. FDA's subsequent 483 response review memo stated that the draft
protocols and proposed corrective actions were considered to be adequate.1
In a related inspection, the FDA similarly observed, "There were no leachable and extractable testing performed for (--redacted--) materials used in buffer preparation."
The drug manufacturer agreed to implement an extractables and leachables assessment policy that included risk assessment,
safety assessment, and model solvent study design, along with generic family-approach studies for leachables and extractables
for the storage of (--redacted--) used in buffer preparation activities.2 This is consistent with BPSA's published recommendations.
At IBC's 7th International Single Use Applications for Biopharmaceutical Manufacturing Conference, held in La Jolla, CA, on
June 14, 2010, Destry M. Sillivan of the FDA provided an update and overview of types of data to be reviewed and specific
areas of concern to the FDA.
Sillivan stated that, "the responsibility for establishing that single-use materials selected for the manufacturing process
do not adversely impact the product falls on the manufacturer of the drug product under review," and recommended that drug
sponsors, "submit sufficient information to provide evidence that the product contacting material does not introduce contaminants
into the product so as to alter the safety, identity, strength, etc."
Following closely the recommendations made in BPSA's 2008 Extractables Guide and FDA CBER training seminar, Sillivan stated that, "CBER recommends a risk-based approach be taken in evaluating extractables
and leachables where you take multiple aspects into account (e.g., indication, safety issues, product characteristics, dosage,
formulation, and stability profile)." If there is no relevant risk associated with the (material in question), "vendor data
can be cross referenced and a detailed justification for the applicability of these data and a justification for no additional
testing should be submitted," he added.
According to Sillivan, "Where there is relevant risk, the drug sponsor may have to determine toxicity based on maximum dosage
of potential leachables based on extractables data. If the maximum dosage of potential leachables presents a safety risk,
leachable evaluation and testing may be necessary. Additionally, if product quality could be affected by potential leachables,
studies may need to be performed to assess the effect on product quality, including efficacy."
New products contacting single-use materials often are reported in the product annual report with no information regarding
material composition, no extractables or qualification studies performed in support of use of the new material, and no written
justification of why the studies that were submitted were appropriate to support suitability for use of the new materials
with the drug product. The FDA and CBER consider this level of information to be insufficient to determine if the change was
The FDA and CBER generally recommend that either the drug sponsor or the material manufacturer demonstrate through sufficient
testing that the material is suitable for the submitted processes and product.