Impurity regs may affect life sciences pipelines, portfolios

By Oliver Steck, principal, and Mayura Gill, senior manager, Risk & Financial Advisory, Deloitte & Touche LLP

During the upcoming July 4^th holiday, many Americans will load their grills with hamburgers, hotdogs, brats, and maybe even some vegetables. As they enjoy those sizzling indulgences, they will likely ingest trace amounts of nitrosamines—naturally occurring organic compounds that can be found in everything from grilled foods to cosmetics to pharmaceuticals.¹ While nitrosamines are considered safe in small quantities, high levels or prolonged exposure could increase the risk of cancer.² Nitrosamines, and other chemicals of concern, are rapidly gaining traction with global regulators and could have a major impact on life sciences companies, their portfolios, their pipelines, and their future go-to-market strategies.³

Nitrosamines can be found in a variety of organic and inorganic compounds that create active pharmaceutical ingredients. They can also be found in some excipients, tablet coatings, and capsules that are used in a variety of therapies.⁴ And the chemicals are not limited to pharmaceuticals. Nitrosamines might also be found in plastics, polymers, rubber materials, and printed surfaces/coatings that are used in the construction of medical devices or their components.⁵

Nitrosamines, titanium dioxide (TiO₂), per- and polyfluoroalkyl substances (PFAS), and benzene/benzoates are making their way onto the chemicals of concern list,⁶ as they have been shown to increase a patient’s likelihood of developing life-threatening conditions such as cancer, as well as negatively impacting fertility and the body’s immune system.⁷

The health risks associated with ingestion and long-term exposure to some of these compounds has been the focus of global regulators and research institutions alike.⁸ These risks have prompted global regulators to consider evolving their legislation to either eliminate the use of these substances all together or place a limit on the acceptable levels used in drug product development, medical devices, and in food and consumer products.⁹ For example, nitrosamines have been found in medications used to treat a wide range of conditions (e.g., hypertension, heartburn, and type 2 diabetes), resulting in at least 10 prominent drugs being recalled.¹⁰

Titanium dioxide has already been banned from food products in Europe, with regulators looking to regulate its use in drug products next.¹¹ Benzene and PFAS are also in the early stages of proposed regulations to limit or ban widespread use, with the potential for a broad sweeping impact to industry.¹² In jurisdictions across the globe such as Europe, US, Canada, Japan and Korea, these regulations are already in effect or are anticipated to be issued through the remainder of the decade.¹³

Core components of a chemicals of concern risk-mitigation program:

What might this mean for pharmaceutical and medical device manufacturers? To uphold the patient safety and efficacy of their products, while maintaining their market authorizations and product supply, manufacturers should try to identify, evaluate, and mitigate these inherent risks in their portfolio. The first step might be to establish formal risk-mitigation programs that include the following core components:

1. Establish a governance and execution framework: Establishing a formalized governance and framework for a risk-mitigation program could be essential for its success. Governance models, program and workstream charters, clear resourcing and communication plans, and scoping evaluations might all be important to properly identify and execute against mitigation options. These programs often stretch across functional groups, requiring collaboration from stakeholders across the company (e.g., research and development (R&D), engineering, commercial, regulatory, quality, legal, procurement, and digital). In some instances, these programs might be large enough that a company will elect to bring in an external project management team to alleviate the administrative/logistical workload and free their specialists to focus on the science.
2. Identify impacted products and assess their risk: An impurity remediation program often begins with a theoretical risk assessment. A company may elect to use a digital solution to evaluate the composition, packaging, or delivery systems of their products and assign a theoretical risk based on each product’s containment of (or capacity to form) chemicals of concern. Documentation of possible attributable risk factors typically follows the risk assessment. The potential impact to manufacturing and distribution sites can then be summarized.
3. Confirm presence of chemicals of concern: The next step might be to conduct extensive and precise scientific testing to confirm the presence of the chemicals of concern in at-risk products. This could include extractable and leachable studies to determine the risk associated with long-term exposure to packaging or drug-delivery materials, lab studies to detect the presence of the chemical in the finished product, or in-vivo testing on mice to determine the mutagenic or toxicologic risks associated with ingestion. Manufacturers could establish global sampling strategies to help facilitate representative testing across the product portfolio and product shelf-life. They could also consider the use of digital tools to centralize data sources and automate reporting. 
4. Establish reformulation/remediation plans and approaches: For products or devices that are confirmed to contain a chemical of concern, a solution might need to be developed to remediate or reformulate the material. These solutions often include identifying replacement compounds or alternate suppliers of device components. It might also require organizations to conduct chemical testing to build further data sets and demonstrate that the chemical of concern is present in low enough quantities that there is no risk to the patient. There is no one-size-fits-all solution to developing these plans because there are a plethora of variables involved. This can include variation in the level of impurities found between batches or between suppliers, availability of alternative compounds, and considerations related to medical necessity and patient impact.
5. Engage global regulators, political groups, trade associations, and industry consortia: Pharmaceutical and medical-device manufacturers should consider adapting a proactive relationship with global Board of Health (BoH) organizations to communicate risk-assessment findings and to outline risk-mitigation strategies and plans. Companies should also consider establishing response teams to address any BoH questions, plan for further testing as needed, and take any required market actions based on the outcome of their risk assessments. Additionally, companies may elect to participate in industry forums to engage with political groups and trade associations to explain their findings and help shape future legislation around chemicals of concern. 
6. Develop lifecycle-management and business-process modifications: Manufacturers should consider implementing network-wide business process training as a part of their business-as-usual strategy. This can help ensure that future products are proactively assessed for potential risks and that manufacturing plants are able to explain their risk-assessment policies and processes in the event of an audit. Other lifecycle-management activities may include the updating of supplier specifications or agreements, the development of a product-release testing strategy or preferred supplier lists, and the creation of a centralized team of subject-matter advisors who can provide support and oversight.

The journey to rid pharmaceutical and medical devices of harmful compounds has only just begun.¹⁴ Over the past few years, some pharmaceutical companies have performed safety assessments on their products to identify impurities. Navigating the future state of chemicals of concern will likely require the coordination of regulators, external advocates, life science companies, and patients to evoke a change toward the purity and sustainability of such products. As the regulatory landscape moves toward stricter restrictions on pharmaceutical impurities, it is important for the industry to be prepared to address new regulations efficiently, with patient safety and maintenance of drug supply at the forefront.

Acknowledgments: Jillian Patane and Mike Giroux

This publication contains general information only and Deloitte is not, by means of this publication, rendering accounting, business, financial, investment, legal, tax, or other professional advice or services. This publication is not a substitute for such professional advice or services, nor should it be used as a basis for any decision or action that may affect your business. Before making any decision or taking any action that may affect your business, you should consult a qualified professional advisor.

Deloitte shall not be responsible for any loss sustained by any person who relies on this publication.

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Endnotes:

¹What to know and do about possible nitrosamines, US Food and Drug Administration (FDA), June 2, 2020

²The truth about the nitrates in your food, BBC, March 12, 2019

³FDA eyes drugs with cancer-causing nitrosamines, USA Today, February 16, 2023

⁴Information about nitrosamine impurities in medications, FDA, November 18, 2021

⁵What to know and do about possible nitrosamines in your medication, FDA, June 2, 2020

⁶Contaminants of Emerging Concern, Interstate Technology Regulatory Council

⁷Chemicals and toxics topics, US Environmental Protection Agency (EPA), December 15, 2022

⁸Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products, AAPS PharmSciTech, February, 2014

⁹European Union: Titanium Dioxide banned as a food additive, US Department of Agriculture, March 3, 2022

¹⁰Drug recalls for nitrosamines could cost big pharma millions, BusinessWeek, September 1, 2022

¹¹Potential EU ban on titanium dioxide would threaten access to drugs, Regulatory News, May 9, 2023

¹²Risk management for PFAS under TSCA, EPA

¹³Per- and polyfluoroalkyl substances, European Chemicals Agency

¹⁴FDA/HESI Research Roadmap Planning on Hazard and Risk Assessment of Nitrosamine Impurities in Drugs, FDA, May 31, 2023

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