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Background: The GRAS Framework

The Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act) was established by Congress in 1958. In the Code of Federal Regulations, the rules that the FDA applies to food additives are spelled out in sections 21 CFR 170.3 and 170.30. A food additive is considered to be any substance that is intentionally added to food or may reasonably be expected to become a component of food, such as leachable components from packaging. These additives are required to be reviewed and approved by the FDA before the additives can be used in food products as part of a premarket approval process.

However, there are exceptions to this review requirement. If the substance is Generally Recognized by qualified experts As having been adequately shown to be Safe (GRAS) under the conditions of its intended use, the substance does not require FDA approval and is not considered a food additive. GRAS assessment can be performed through scientific analysis, or from safe historical consumption of the substance if it has been used in food prior to 1958.

The Self-Affirmation Pathway and Its Controversy

Since 2016, the FDA has operated a voluntary GRAS notification program.  Under this system, any qualified individual can notify the FDA that a substance is not subject to the premarket approval process as it is considered GRAS. The FDA may not question the basis for the GRAS conclusion, or it may conclude that there is insufficient information to make a GRAS conclusion.

Although the FDA had a GRAS affirmation process in place around 1972, it was discontinued by 1997 due to lack of resources and was replaced with the notification process. The FDA maintains a GRAS database of notifications. The GRAS list, which is not comprehensive, is located in 21 CFR 182, 184, and 186.[1] Notably, the GRAS notification process is voluntary, and does not require either notification or affirmation from the FDA.

This self-affirmation pathway has been criticized as a “loophole,” enabling manufacturers to introduce new food ingredients without sufficient safety data or transparency. While the process allows for efficiency and rapid market entry, it also means that the FDA and consumers may be unaware of new substances in the food supply.

Proposed Changes in 2025

In March 2025, the Health and Human Services secretary directed the FDA to consider removing the self-affirmation process of the GRAS program.[2] Companies would need to publicly notify the FDA of their intended use of substances in food products, along with safety data, before they could go to market with the substances. This substantial change in legislation would require many companies to re-evaluate their safety data and may require retroactive approval from the FDA.

Current vs. Proposed GRAS Process

Implementing these changes will not be immediate. The FDA must conduct formal rulemaking, and because the GRAS exemption is written into federal law, Congressional action may be required. These steps could take years and may face industry resistance and legal challenges.

Establishing Safety Profiles for Food Additives

• Deliberately Added Ingredients: Toxicological evaluation of the ingredients based on the chemistry and amount can assist in establishing the safety profile.
  
  
• Inadvertent Additives (e.g., from Packaging): Inadvertent food additives may be introduced from materials contacting food products, including food processing equipment, containers, or food preparation surfaces. In these cases, substances may diffuse into the food from the contact materials, which are often plastic and may contain antioxidants, colorants, plasticizers, and other stabilizers. For these substances, migration testing needs to be performed using food simulants to assess the amount of substance that is anticipated to be incorporated into the food product. This testing is comparable to leachables/extraction testing performed for medical devices.

Contact Cambridge Polymer Group for questions about migration testing in plastic products used in food contact.

On May 6, 2025, the ASTM Workshop on the Characterization of Hydrogel Medical Devices brought together researchers and engineers to discuss current test methods for hydrogels in medical devices. Led by Stephen Spiegelberg of Cambridge Polymer Group, the workshop focused on current test methods, industry challenges, and the need for new standards.

Why Are ASTM Standards and Workshops Important?

ASTM standards play a crucial role in the medical device industry by:

• Establishing best practices for testing methods for researchers, especially those new to the field.
• Improving repeatability and accuracy across different laboratories.
• Assisting regulatory agencies in verifying the quality and reliability of submitted data.
• Providing companies with confidence that their test methods will withstand regulatory scrutiny.

ASTM workshops are designed to:

• Share the latest understanding and best practices on the topic area within the industry.
• Gather feedback from regulators on test methods to facilitate regulatory clearance.
• Identify gaps in current testing methods and associated standards.
• Establish task groups to develop new and improved standards.

Identifying Hydrogel Gaps and Needs in Hydrogel Characterization

A notable finding of the May 6th workshop was that only two relevant standards for hydrogel testing currently exist across ASTM, ISO, and USP. This lack of established guidance highlights a significant unmet need, especially as hydrogels are being used more often as structural components rather than just as coatings.

The workshop presentations covered a range of topics, including:

• Chemical risk analysis of hydrogels
• Development of animal models for safety and effectiveness testing
• Evaluation of high-water-content hydrogels
• Characterization of degradable and specialized hydrogels

Standardization Priorities

During a closing discussion led by co-chair Jon Moseley, participants identified several top priorities for new standards, with the development of a common terminology for hydrogels emerging as a particularly urgent need. Inconsistent language can create confusion among manufacturers, regulators, and end users, so establishing clear definitions is essential.

Other priorities for standardization include:

• Friction measurements
• Mechanical testing methods
• Dynamic property assessment (rheology and DMA)
• Accelerated aging protocols
• Environmental conditioning
• Chemical risk assessment, particularly regarding solvent selection

Mechanical testing and accelerated aging generated the most discussion, as they appear to be the most challenging currently. Chemical risk assessment was also a discussion, particularly with regards to solvent selection for chemical characterization. Task groups are being formed to address these topics, and participation from those with relevant experience is encouraged.

Looking Forward: Opportunities and Advice

For those new to hydrogels, it’s important to recognize that standard test methods for other polymers, such as thermoplastics, elastomers, and thermosets, may not be suitable due to hydrogels’ unique properties and greater batch-to-batch variability. As one participant aptly summarized,

“Hydrogels always find a way to mess with you.”

Manufacturing hydrogel devices presents ongoing challenges related to their compliance, temporal variability, and unique chemistries. As hydrogels are used in more advanced applications, such as degradable implants or piezoelectric devices, the need for robust, widely accepted testing standards will only grow. Regulatory requirements are currently quite stringent for hydrogels, particularly degradable ones, due in large part to lack of industry-wide experience with these materials. 

Collaboration between experienced developers and regulatory agencies will be vital as new standards are developed. If you are interested in contributing to these efforts, please contact Cambridge Polymer Group at info@campoly.com. Stay tuned for further updates as the ASTM task groups work to advance hydrogel testing standards and support innovation in medical device development.

ASTM International will host the Workshop on the Characterization of Hydrogel Medical Products on May 6, 2025, in Toronto, Canada, during the spring meeting of the ASTM Committee F04 on Medical and Surgical Materials and Devices. This event brings together leading experts to discuss best practices, emerging analytical techniques, and the urgent need for standardized testing methods for hydrogels used in medical devices.

Workshop Focus and Objectives

Hydrogels are increasingly vital in medical applications, from regenerative medicine to implantable devices, due to their unique properties as water-swollen, three-dimensional polymer networks. However, the lack of standardized characterization protocols presents challenges for manufacturers, regulators, and researchers. The workshop aims to:

• Review current analytical techniques for hydrogel characterization, including assessments of chemistry, morphology, mechanical properties, and in-use performance.

• Identify critical gaps in existing ASTM standards and discuss the need for new or improved test methods, particularly those relevant to both implantable and non-implantable hydrogel medical products.
  
  
• Foster collaboration among engineers, chemists, scientists, regulators, and industry stakeholders to advance the field and improve product safety and efficacy.

Who Should Attend

This workshop is designed for professionals involved in the development, testing, and regulation of hydrogel-based medical products, including:

• Medical device manufacturers

• Testing laboratories

• Regulatory agencies

• Pharmaceutical companies utilizing hydrogel technologies

Interactive Discussion and Next Steps

Attendees are encouraged to participate in an open discussion at the conclusion of the workshop to help shape the future of hydrogel test standardization. This collaborative session will be instrumental in determining priorities for new ASTM standards and identifying opportunities for further research and interlaboratory studies

Workshop Co-Chairs

• Stephen Spiegelberg, Cambridge Polymer Group

• Jon Moseley (Retired)

Featured Speakers and Presentations

Join the Conversation

Be part of the effort to shape the future of hydrogel medical product standards. Your expertise and input are vital to ensuring the safe and effective use of these soft materials in healthcare. For full event details and registration, visit the ASTM Workshop on the Characterization of Hydrogel Medical Products information page.

Microplastics have become a pressing topic in environmental and health discussions, with increasing attention from the media and scientific community. These tiny plastic particles, typically defined as ranging in size from 1 micrometer to 5 millimeters, can be composed of various types of polymers and are now being detected in an array of consumer products. A recent study by Huang et al. (2025)[1] examined the presence of microplastics in intravenous (IV) infusion bags, a common component of medical treatment.

What Are IV Infusion Bags?

IV infusion bags are flexible containers designed to deliver aqueous solutions, such as drugs, electrolytes, or saline, directly into a patient's bloodstream. Given their direct interaction with the body, the potential presence of microplastics in these containers may be of concern.

Key Findings from Huang et al.'s Study

Huang's study focuses of two brands of saline IV bags made from polypropylene. The contents of these bags were filtered, and the researchers employed Raman spectroscopy, scanning electron microscopy (SEM), and optical microscopy to identify and quantify the particles in the filtrate. The Raman spectroscopy confirmed that the particles were polypropylene. Particle counts revealed concentrations between 7020-7900 particles per liter of saline, with the majority (68%) measuring between 1-10 micrometers, and an overall size range of 1-62 micrometers.

The study did not speculate on how these microplastics entered the IV bags.

Health Implications

The authors note that microplastics have previously been discovered in human blood and adjacent organs, including the lungs, liver, kidneys, and spleen. Scientists at Cambridge Polymer Group are actively engaged in identifying and quantifying microplastics in products and tissues and in a recent study, we have detected microplastics in multiple lung tissue samples. The health implications of these microplastics remain uncertain at this time.

Regulatory Standards for Particulates

According to USP Particulate Matter in Injections, the limits for particles exceeding 10 micrometers should not surpass 12,000/L and 2,000/L for particles greater than 25 micrometers in containers holding more than 100 ml of solution. For containers with less than 100 ml, the limits are set at 3,000 particles (>10 micrometers) and 300 particles (>25 micrometers) per container. While the concentrations of microplastics found in Huang's study fall within these regulatory limits for larger particles (>10 micrometers), the sheer number of smaller particles raises questions about whether current standards adequately address this emerging issue.

What’s Next?

The detection of microplastics in IV infusion bags highlights a critical gap in our understanding of their potential health impacts. Further research is needed to explore:

1. How microplastics enter medical products during manufacturing or storage.
2. The long-term effects of introducing microplastics into the human body through medical treatments.
3. Whether existing regulatory standards should be updated to account for smaller particles.

As scientists continue to investigate this issue, healthcare providers and manufacturers must remain vigilant about minimizing contamination risks. In parallel, regulatory bodies may need to revisit particulate limits to ensure patient safety in light of emerging evidence on microplastics.

By shedding light on studies like Huang et al.'s, we can better understand and address this growing concern—ensuring that medical products meet the highest standards of safety and efficacy.

Companies regularly rely on third-party laboratory testing data to support regulatory medical device and pharmaceutical submissions, particularly when lacking in-house expertise or facilities. The credibility of these third party laboratories is crucial to regulatory success, but recent actions by the FDA highlight the risks associated with unvetted or noncompliant third party data.

Escalating FDA Scrutiny on Data Integrity

The FDA recently published warning letters to laboratories in China and India with concerns about fraudulent or unreliable testing data from these laboratories. One warning letter to a Chinese laboratory[1] concerned data from cytotoxicity and sensitization studies conducted on different dates with nearly identical results, raising suspicion that the data was not genuine. A series of letters released to an Indian laboratory in 2024 and 2025 notified pharmaceutical companies that any in vitro studies conducted by this laboratory for new drug applications and abbreviated new drug applications must be repeated at different study sites that do not have data integrity concerns.[2]

These warning letters reinforce a memo released from the FDA in February, 2024, warning medical device manufacturers to carefully examine data from third party laboratories to ensure the data is reliable.[3]

“The FDA has noted an increase in unreliable testing data generated by third-party testing facilities on behalf of device manufacturers and sponsors. This has resulted in the FDA being unable to reach a substantial equivalence determination or otherwise authorize marketing for medical devices whose submissions rely on such data.” — FDA Notification, March 2025[4]

Consequences for Manufacturers and Patients

This surge in data integrity issues has led the FDA to reject entire submissions, preventing the agency from reaching substantial equivalence determinations or authorizing marketing for affected medical devices. When the FDA cannot rely on submitted data, not only are sponsors forced to repeat costly studies, but patient access to new devices is also delayed, and supply chains may be disrupted.

Cambridge Polymer Group’s Commitment to Data Integrity

At Cambridge Polymer Group, we recognize the regulatory and reputational risks associated with unreliable data. Our protocols follow published standards, with calibrated, verified equipment, rigorous data checks, and comprehensive review processes. All raw and processed data, as well as equipment information, are available for client and regulatory inspection, ensuring transparency and readiness for regulatory review.

Conclusion

The FDA’s ongoing focus on data integrity makes it clear: the cost of unreliable third-party testing is high, with potential for regulatory setbacks, financial loss, and reputational harm. Selecting a transparent, compliant, and reliable laboratory partner is essential for successful regulatory submissions and for maintaining patient and market trust.

Traditional headlamps (worn above) are cumbersome and don't accommodate face shields.

A groundbreaking surgical task light has been introduced by MezLight in collaboration with Syensqo[1], demonstrating a thoughtful approach to product design by considering key factors such as:

• Customer needs
• Sustainability concerns
• Environmental durability
• Material suitability

Addressing Customer Needs: Enhanced Usability and Safety

Traditional surgical task lights are typically worn as headlamps by surgeons (see image above), which can become uncomfortable and cumbersome during extended procedures. The new MezLight task features an adjustable arm allowing for precise positioning and eliminating the burden of a headlamp. This design also accommodates the use of face shields, thereby prioritizing both usability and safety for surgeons.

Sustainability: Built for Repeated Use

In terms of sustainability, the task light has been engineered to withstand repeated cleaning and sterilization through steam sterilization using an autoclave, successfully enduring over 100 autoclave cycles. This capability ensures a long lifetime of repeated cleaning cycles for the product. As a result, the light has been designed to be robust enough for mechanical positioning and adjustment during surgical procedures over many repeated uses.

Material Selection: Meeting Rigorous Medical Standards

To meet the stringent requirements for mechanical performance and sterilization, the design team chose Radel®, a polyphenylsulfone (PPSU) supplied by Syensqo. This material was selected based on its exceptional properties:

• High heat deflection temperature of 207°C, ensuring stability under autoclave conditions and preventing deformation from the LED heat source.
• Good hydrolytic stability, enabling it to withstand repeated exposure to high-temperature steam without degradation
• Impact strength comparable to other durable plastics such as polycarbonate, ensuring mechanical integrity during use.

Radel® has also been historically used in surgical instrument handles and trays, proving its ability to endure multiple sterilization cycles.

A Model of Comprehensive Design

This surgical task light exemplifies the comprehensive considerations involved in material selection for medical products, while ensuring the fulfillment of customer needs. By addressing the unique challenges faced in surgical environments, this product not only meets the practical demands of healthcare professionals but also aligns with sustainability goals in medical device manufacturing.