Over the past few years nitrosamines and nitrosamine impurities have been increasingly gaining the reputation of being high-risk containments in the food industry. These molecules of interest also impacted the pharmaceutical industry, and pharmaceutical companies faced a requirement to rapidly adopt risk mitigation plans to monitor the presence of nitrosamines in drug products. Nitrosamines have garnered significant attention from the pharmaceutical industry due to their detection in commonly prescribed medications for conditions like type 2 diabetes, high blood pressure, and heartburn. [1]To mitigate the potential presence of nitrosamine impurities in pharmaceuticals, manufacturers are now facing impending regulatory requirements in various markets – in the European Union, for example, they were obligated to submit reformulation strategies and mitigation plans in late 2022.[2].
Research is raising concerns about PFAS use
Similarly, PFAS (per- and polyfluoroalkyl substances) in pharmaceutical packaging have recently come under scrutiny, leading to significant regulatory changes. The food sector has already initiated the publication of preliminary regulations aimed at restricting PFAS in packaging.[3]. Key figures in the food industry are taking a proactive and voluntary approach, strategically seeking alternative packaging solutions to address the impending regulatory constraints related to PFAS on surfaces that come into contact with food.[4]. Can we expect a comparable action to follow suit in the pharmaceutical industry in regards to primary or even secondary packaging?
PFAS comprise of a group of synthetic compounds known for their robust fluorine-carbon bonds. This distinctive quality imparts resilience and durability to PFAS, making them valuable for diverse industrial uses, including pharmaceutical packaging. Examples include blister packaging found in stoppers, plungers, or seals for injectables. These primary packaging materials can prove difficult to find alternatives that provide an impactful barrier against extractables and could also trigger a full requalification from health regulators for approved products.[6].
The characteristics of this family of molecules, while beneficial for industrial products, increase the likelihood of bioaccumulation and a slow decomposition rate for these products. As scientists worldwide continue to study the effects of PFAS compounds on human and ecological health, these chemicals have been recognized as a group that can pose health concerns and act as endocrine disruptors.[5] Research is beginning to link PFAS to an increase in kidney cancer rates, reproductive challenges, and thyroid issues.[5]
Regulatory developments and their impact
In January of 2023, Denmark, Germany, the Netherlands, Sweden, and Norway proposed an EU-wide ban on a large cache of per- and polyfluoroalkyl substances (PFAS) under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH).[7] This marks a significant milestone in the initiation of regulations for this class of substances within the pharmaceutical sector. Currently, the proposed regulatory ban would apply to raw materials, excipients, and packaging.[7]. However, this regulatory ban does not impact active pharmaceutical ingredients (APIs).[7]
It will be essential to closely observe how this will affect the regulatory landscape for CMC (Chemistry, Manufacturing, and Controls) in both primary and secondary packaging. How will this impact approved products, and will this result in many products needing to undergo requalification for their primary or secondary packaging? With Europe taking the lead in introducing draft regulations on PFAS, will other countries and regions implement their own regulations?
Hedging uncertainty through awareness of regulations
The global regulatory environment is dynamic and can undergo rapid changes. Adapting to these changes often necessitates significant adjustments in response strategies. When dealing with new draft regulations, there is frequently a need for clarification on various aspects, including:
- What adoption timelines will look like
- How new regulations will be implemented on a local scale
- The exact permissible amounts
Last year, a prominent pharmaceutical company encountered a significant challenge in navigating global regulation changes. Through a collaborative effort with CMC Intelligence, they bolstered their internal team’s understanding of emerging draft regulations. This collaboration allowed their teams to remain well-informed of evolving regulatory changes and afforded them the necessary time to adapt their internal processes to ensure compliance with the evolving standards. With the introduction of a new CMC Intelligence entitlement to address post-approval changes, Clarivate now covers a broader range of the lifecycle of pharmaceutical products.
“Cortellis CMC Intelligence changes the way we work in reviewing regional regulatory requirements by making complex content available in a simplistic view. This enables Reg CMC to be more efficient and effective in risk management, strategic decision-making with stakeholders, and it also increases our compliance and speed to market.”
Implications for stakeholders:
As regulations evolve, so must the industry. Manufacturers, healthcare providers, and consumers alike face the need to quickly adapt. Future research could focus on developing PFAS-free packaging materials that meet regulatory standards without compromising safety. A proactive approach in understanding regional regulatory requirements and strategic decision-making with stakeholders is crucial for maintaining compliance and market speed.
A chance to innovate:
Global health impacts our world and there are various stakeholders making choices, from manufacturers to healthcare providers and patients. Impending change affords an opportunity for innovation. Taking a proactive approach with regard to potential regulation of PFAS materials could benefit all stakeholders. By leading the charge in implementing PFAS-free packaging solutions, industry can stay ahead of any incoming regulatory requirements and ensure safe materials are used in products. This will take efforts from all within the supply chain, from the R&D of new packaging materials to the documentation detailing a change in practice for post-approval manufacturing.
Clarivate is poised to provide regulatory solutions to help navigate a proactive approach to change. Learn more about the Clarivate Cortellis CMC Intelligence offering here.
References:
[1]Li K, Ricker K, Tsai FC, Hsieh CJ, Osborne G, Sun M, Marder ME, Elmore S, Schmitz R, Sandy MS. Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications. Int J Environ Res Public Health. 2021 Sep 8;18(18):9465. doi: 10.3390/ijerph18189465. PMID: 34574388; PMCID: PMC8467924.
[2]Nitrosamine impurities | European Medicines Agency (europa.eu)
[3]Per- and polyfluoroalkyl substances (PFAS) – ECHA (europa.eu)
[4]The PFAS Packaging Predicament: McDonald’s Isn’t Loving It | AIER
[5]PFAS Exposure and Risk of Cancer – NCI
[6]European PFAS ban would burden manufacturers (pharmaceutical-technology.com)
[7]Registry of restriction intentions until outcome – ECHA (europa.eu)
