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Volume 40, Issue 3
Standardized testing protocols are crucial for acceptance of single-use systems.
Single-use systems (SUS) featuring plastic components and materials are widely used in bio/pharmaceutical development and clinical-trial material manufacturing, and are expected to become more common in commercial manufacturing. Drug manufacturers and contract manufacturers favor SUS for the benefits of fast changeover, reduced cross contamination, and manufacturing system flexibility.
Concern about the potential for contaminants from the plastic materials interacting with the drug, unacceptable extractables data, and a lack of standards for evaluating SUS materials could, however, slow adoption.
Nearly three-quarters of biopharmaceutical manufacturers surveyed for the 2015 BioPlan Associates industry study (1) identified extractables and leachables as a concern that may limit further use of SUS. The only greater concern was breakage of bags and loss of production material. Concerns about extractables and leachables have been steady during recent years, partially due to the increased use of disposables and increased awareness of the uncertainties about related regulatory issues, according to the report.
Current good manufacturing practices (CGMPs) require that manufacturing equipment must be constructed so the surfaces that contact components, in-process materials, or drug products “must not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product” (2). For biologic products, “All surfaces that come in contact with products shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use” (3). Similar requirements are in place for the European Union (4).
Therefore, bio/pharma and contract manufacturers must--using scientific- and risk-based approaches--test the materials and surfaces that come in direct or indirect contact with the API, ingredients, and drug product to demonstrate equipment and process suitability for regulatory filings.
Extractables studies identify chemicals that migrate from a material when exposed to a solvent at an elevated temperature, generating a worst-case test for contaminants. The data are used to assess toxicities of the extracted chemicals and to assess the potential for leachables--compounds that migrate into a specific drug product or process under normal conditions during the drug product’s lifecycle.
Some suppliers of manufacturing components and packaging materials provide extractables data that can be used for preliminary screening and risk assessment; however, the information often is not available or sufficient. A complex supply chain, where different parts of an SUS technology may be manufactured or processed by multiple subcontractors at multiple locations, adds uncertainty to the quality and completeness of the data.
In the BioPlan study, more than 80% of the respondents “agreed” or “strongly agreed” that vendors of SUS should generate and validate extractables and leachables data. The study authors concluded that drug owners believe SUS vendors need to do more testing and analysis of materials used in SUS devices, or they are not comfortable dealing with extractables and leachables issues and defer to suppliers for the testing (1).
The cost of acquiring data was also considered. Nearly one-third of the respondents said they would not pay SUS suppliers more for extractables and leachables data; 22% said they would pay up to 25% more. The estimated average upcharge was 13.4%. The study authors attributed the drug manufacturers’ price sensitivity to SUS-supplier upcharges for data to general cost-consciousness, increased knowledge about regulatory issues, a better assessment of developing the data internally, and an increasing number of contract service providers offering testing services of extractables and leachables.
Willingness to pay a markup for data has largely stabilized, the study concludes, although a growing number of drug owners are willing to do their own testing for early-phase development, where data requirements are less stringent.
The lack of sufficient extractables data from suppliers of SUS has spurred activity for standardized testing protocols for these technologies. Representatives of drug manufacturers, testing laboratories, SUS manufacturers and suppliers, independent consultants, and regulatory authorities have participated in discussions, authored position papers, proposed best practices and standards, and developed databases. Often, the proposals conflict on key points; however, the groups are reporting efforts to build consensus.
The Product Quality Research Institute (PQRI), a collaborative effort of FDA’s Center for Drug Evaluation and Research (CDER), industry, and academia, has published several documents including safety thresholds and best practices for extractables and leachables in orally inhaled and nasal products (5), and a similar publication for parenterals and ophthalmic drug products (6).
Bio/pharma and medical-device companies formed the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium to compile toxicological data on leachables and extractables to study their impact on drug product packaging, delivery, and manufacturing systems. As of October 2015, the consortium had developed a database of nearly 400 compounds listing chemical, chronic toxicity, mutagenicity/carcinogenicity, reproductive/developmental toxicity, and absorption, distribution, metabolism, and excretion information (7).
An ELSIE materials working group also piloted an extraction study protocol on polyethylene and polyvinyl chloride that included extraction solvents, extraction techniques, and a range of analytical techniques. The study investigated whether a reduced number of extraction techniques or a reduced number of solvents could be used to obtain information useful for material selection, regardless of product type (8).
Trade associations, including the Parenteral Drug Association and the International Society of Pharmaceutical Engineers, also have been active in sponsoring presentations and publishing papers about extractables and leachables testing.
Proposals and consensus
The Bio-Process Systems Alliance (BPSA), a corporate member trade association of component suppliers, systems integrators, users, and testing laboratories, was founded in 2005 to accelerate the adoption of single-use manufacturing technologies. Representing the industry supplier market segment, BPSA has published recommended practices for extractables and leachables testing and has initiated efforts to standardize testing procedures for other aspects of SUS materials (9).
The BioPhorum Operations Group (BPOG), which represents the drug-owner segment of the industry, defined a standardized extractables testing protocol for SUS manufacturing systems that covers methods for extractables testing studies, including sample preparation, extraction conditions, and reporting data. The authors, members of the BPOG extractables working group, wrote that a testing protocol, with agreed-upon test methods, would establish common expectations among suppliers, users, and regulators on the type of testing data to be generated. The enhanced data would help users compare components from different suppliers, would assist suppliers in selecting materials that end users need, and would help in controlling product variability (10).
Following publication of the BPOG paper, BPSA published a perspective article noting a difference of opinions among end-user companies, suppliers, testing laboratories, and standards-writing bodies that must be resolved to achieve a full industry consensus standard (11).
Representatives of BPSA and BPOG are participating in an ASTM International working group developing practice documents for extractables studies. The extractables test solutions practice will define a standard method to create extraction samples from single-use bioprocess systems using model bioprocess extraction solutions. Data generated from these studies could be used to make risk-based decisions about the potential impact on the API or drug product and the selection of equipment or components. Analysis of extractables test solution will be covered in a separate practice (12).
ASTM is also developing a practice for testing of leachables for single-use materials that contact APIs, intermediates, or the final drug product. The studies are designed to provide a leachables profile based on testing methodology comparable to extractables studies (13).
1. BioPlan Associates, 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (Rockville, MD, April 2015), www.bioplanassociates.com/12th 2. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.65(a).
3. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 600.11 (b).
4. EudraLex, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (Brussels, Belgium, August 2014).
5. PQRI, Safety Thresholds and Best Practices for Extractables and Leachables In Orally Inhaled and Nasal Drug Products (September 2006).
6. D. Paskiet, PDA J. Pharm. Sci. Technol, 67 (5) 430-47 (2013).
7. Extractables and Leachables Safety Information Exchange, online www.elsiedata.org/elsie-database/, accessed Feb. 26, 2016.
8. A. Teasdale, et al., AAPS PharmSciTech, 16 (3) (June 2015).
9. BPSA, Technical Guides, Extractables and Leachables, online www.bpsalliance.org, accessed Feb. 26, 2016.
10. W. Ding, et al, Pharm. Eng, 34 (6) (2014).
11. BPSA, Toward Industry Standardization of Extractables Testing for Single-Use Systems: A Collective BPSA Perspective, (March 10, 2015) online, www.bioprocessintl.com, accessed Feb. 21, 2016.
12. ASTM WK43975, “New Practice for Determining and Characterizing BioProcess Extractables from Components, Subassemblies, and Assemblies Used in Single-Use Applications,” ASTM International, www.astm.org (West Conshohocken, PA), accessed Feb. 22, 2016.
13. ASTM WK48084, “New Practice for Determining and Characterizing Leachables released from Materials used in Single-use Systems under bioprocess operating conditions,” ASTM International, www.astm.org (West Conshohocken, PA),
accessed Feb 22, 2016.
Vol. 40, No. 3
When referring to this article, please cite it as R. Peters, "Building Consensus for E&L Testing Standards," Pharmaceutical Technology 40 (3) 2016