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.
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 µm 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 submitted appropriately.
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.