June 8, 2023
Advanced therapies are a crucial component of an
emerging pharmaceutical toolbox. These new and novel drugs are often the last line of treatment for patients with rare and intractable diseases. As such, they require complex production processes to ensure they can address patient needs at the right time. As key players in enabling the design and development of these fragile, potentially life-saving biologic drugs, single-use technology (SUT) suppliers must align with advanced therapy manufacturers to de-risk single-use manufacturing processes and chemical composition requirements to maintain the safety and efficacy of new treatment innovations.
The Additives that Impact Therapeutic Manufacturing
Historically, SUTs used in the manufacture of advanced therapies and other medical innovations utilize chemicals that have been recently identified as potentially impactful to human and environmental health. Phthalates (THAL-ates), a family of chemicals that have commonly been incorporated into plastics and polymer-based materials to increase flexibility and durability, are known to impact human health. These endocrine-disrupting chemicals are also slow to naturally biodegrade.1 Due to these concerns, many industries (e.g., children’s toys, food packaging) 2, 3 are gradually replacing phthalates—also known as “plasticizers”—with alternative chemicals in their manufacturing processes, if not outright banning them.
To reduce and ultimately eliminate the use of these materials, the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation in the European Union (EU) “aims to protect human health and the environment by restricting dangerous substances and articles made of those substances,” 4 including phthalates. In March of 2018, the EU announced the restriction of three phthalates: di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and butylbenzyl phthalate (BBP), and adding a fourth diisobutyl phthalate (DIBP), within Annex XVII of REACH. While the U.S. Food and Drug Administration (FDA) has issued guidance cautioning against their use, phthalates such as DEHP can still be found in many SUTs that support the manufacture and delivery of therapeutic drugs.
Evidence that patients are routinely exposed to phthalates like DEHP in the course of their medical care is well-established. 5, 6 In 2017, the EU adopted regulations requiring a benefit-risk assessment be conducted before certain phthalates (including DEHP) can be incorporated into medical devices; the FDA likewise issued guidance in 2002 recommending that healthcare providers “consider alternatives” to DEHP, though more stringent requirements have yet to be required for products manufactured and distributed in the United States market. That reality is likely to change in the future as more calls to shift regulation emerge.
For example, in 2021, several members of the U.S. House of Representatives issued a letter to the FDA urging the agency to review its 2002 guidance and adopt more stringent requirements around the use of phthalates. 7 In California, DEHP has been designated as a reproductive and developmental toxicant and a carcinogen; the state advises consumers to request DEHP-free devices when undergoing medical treatment.8
Redesigning Single-use Solutions for the Future
Charter Medical, an innovative single-use solutions developer and supplier for cell therapy manufacturers, continues to prioritize DEHP-free materials selection in the design and development of its standard and custom polymer-based processing solutions such as bags, tubing, transfer sets, overmolds, and manifolds used in cryogenic and cell expansion applications in accordance with global regulatory directives intended to protect the environment and human health. The removal of DEHP and other additives from these cell therapy processing components will contribute to a safer future for single-use solutions.
By partnering with customers to meet their standards for materials development—especially in the absence of current industry-wide standards—Charter Medical is committed to addressing the ever-evolving needs of an increasingly complex advanced therapies market. Eliminating additives like DEHP is a critical step to helping cell and gene therapy innovators take a forward-thinking approach to meeting emerging patient health and safety requirements.
References
1. National Institute of Environmental Health Sciences. Endocrine Disruptors. Retrieved April 28, 2023. https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
2. Brown, P., KrennHrubec, K., Casciotti, D., … & Fox-Rawlings, S. (Revised 2022). Phthalates and Children’s Products. National Center for Health Research. Accessed June 1, 2023, from https://www.center4research.org/phthalates-childrens-products/
3. U.S. Food & Drug Administration. (Revised 2022). Phthalates in Food Packaging and Food Contact Applications. Accessed June 1, 2023, from https://www.fda.gov/food/food-ingredients-packaging/phthalates-food-packaging-and-food-contact-applications
4. European Chemicals Agency. Understanding Reach. Retrieved May 26, 2023. https://echa.europa.eu/regulations/reach/understanding-reach
5. Kaestner, F., Seiler, F., Rapp, D., Eckert, E., Müller, J., Metz, C., … & Göen, T. (2020). Exposure of patients to di(2-ethylhexy) phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy. Plos one, 15(1), e0224931.
6. Ruzickova, K., Cobbing, M., Rossi, M., & Belazzi, T. (2004). Preventing harm from phthalates, Avoiding PVC in hospitals. Health Care Without Harm.
7. Udasin, S. (2022, January 10). FDA must address endocrine-disrupting phthalates: House Oversight. The Hill. Retrieved March 31, 2023, from https://thehill.com/policy/equilibrium-sustainability/589034-fda-must-address-endocrine-disrupting-phthalates-house/.
8. California Office of Environmental Health Hazard Assessment. (n.d.). Di(2-ethylhexyl) phthalate (DEHP). P65warnings.ca.gov. Retrieved March 31, 2023, from https://www.p65warnings.ca.gov/fact-sheets/di2-ethylhexylphthalate-dehp#:~:text=California%20law%20prohibits%20the%20manufacture,law%20has%20a%20similar%20prohibition.
Additional Resources
· Regulation MDR 2017/745: Melvin, T. (2022). The European Medical Device Regulation–What Biomedical Engineers Need to Know. IEEE Journal of Translational Engineering in Health and Medicine. Retrieved May 31, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395138/
· IVD Regulation 2017/745: Kahles, A., Goldschmid, H., Volckmar, A., … & Stenzinger, A. (2023). Structure and content of the EU-IVDR. Springer Nature. Retrieved May 31, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9896441/
About The Author
Jay Collins, MBA, CAPM®, is the Product Manager at Charter Medical in Winston-Salem, North Carolina. Jay is responsible for managing Charter’s single-use portfolio, introducing new products, and providing cross-functional project leadership. Jay leverages his experience in market research, product operations, and product management in the medical device and single-use industry to drive product-led growth in global markets. Jay has a B.S.B.A. from the University of North Carolina at Charlotte and earned his MBA from Appalachian State University in Boone, NC.
About Charter Medical, LLC
Charter Medical, part of the Solesis family of companies, specializes in designing and manufacturing customizable single-use solutions for the advanced therapy, bioprocessing, and blood management markets. As an ISO 13485-certified and FDA-registered company, we provide high-quality, innovative solutions and services that support biological fluid handling, cell growth, and cryopreservation processing steps from early-stage development to scale-up for commercialization. From bio-containers and fluid transfer sets to filters and manifolds, Charter’s solutions help life sciences innovators turn bold ideas into lasting breakthroughs that enable industry-leading companies to bring their life-saving therapies to market.
Operating in North Carolina, USA, Charter Medical employs more than 150 employees between two sites in Winston-Salem.