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NAMSA, a medical device contract research organization, announced last week the acquisition of the US medical device testing operations of WuXi AppTec, a biopharmaceutical and medical device testing laboratory headquartered in China. This acquisition is part of a recent trend of acquisitions of medical device testing laboratories by larger multinational testing conglomerates over the past few years. This trend, predicted to continue, results in larger, consolidated operations with higher volumes and the ability to offer routine standardized testing on complex projects. However, it comes with a cost.

Challenges in Biological Safety Evaluation

Evaluation of the biological safety of medical devices with compliance to new standards and revisions of existing standards has become increasingly challenging.  Given the shift in regulatory expectations, along with an increase in the use of unique materials and manufacturing processes, each premarket submission often requires a custom-designed strategy for assessing biological safety that takes in to account the details of the device’s indication and composition.  This approach dictates constant communication between engineers and regulatory affairs specialists at the medical device manufacturer, the research lab conducting the biological endpoint and chemical characterization testing, and the toxicologists and biologicals safety specialists conducting the biological evaluation and making a final determination on safety.

CPG’s Collaborative Approach to BSE

Material scientist and biocompatibility specialists at Cambridge Polymer Group work directly with the client through the submission process to ensure a successful outcome with regards to evaluation of the biological safety of the device.  Although communication often begins with a conversation between a single engineer at a medical device company and a scientist at CPG, CPG in-house experts often become part of the cross-functional team that is necessary to effectively address FDA feedback. As needed, CPG can also rapidly bring in additional external expertise to further support the submission process.

The customer-driven, interactive approach offered by CPG has resulted in a high success rate with premarket submissions. Ultimately, the support offered by in-house experts at CPG, along with external partners to CPG, can reduce the timeline and overall cost for bringing a medical device to market.  Turnkey contracts for biological safety evaluation may increase the risk that the premarket submission does not meet current regulatory expectations.

The recent announcement of INEOS's decision to permanently close its ABS (acrylonitrile butadiene styrene) production facility in Addyston, Ohio, has sent ripples through the medical device manufacturing industry. This closure, set to begin in the second quarter of 2025, will significantly impact manufacturers who rely on ABS plastics for various medical applications. The situation calls for a comprehensive strategy to address supply chain challenges and regulatory requirements.

Understanding ABS and Its Applications in Medical Devices

ABS is a versatile thermoplastic polymer widely used in the medical device industry due to its durability, chemical resistance, ease of processing, and biocompatibility. Applications include:

• Diagnostic equipment housings, including imaging machines and laboratory instruments
• Drug delivery devices, such as nebulizers, auto-injectors, and portable drug delivery systems
• Intravenous Access Devices, including components of IV connectors and luers
• Respiratory care devices, such as ventilator valves, medical masks, and tracheal tubes
• Non-absorbable sutures and tendon prostheses

ABS can be sterilized using methods like ethylene oxide gas, gamma radiation, or steam. The material can be easily colored and shaped to meet specific design requirements.

Challenges for Medical Device Manufacturers: Supply Chain Disruptions

The closure of the Addyston facility may lead to potential shortages and longer lead times for ABS materials. Manufacturers will need to diversify their supplier base and potentially look for alternative sources.

Cost Implications: A change in the ABS supplier could result in ship holds during qualification of a new supplier, resulting in a loss of profit from medical device sales. Further, the supplier change could impact material costs, potentially affecting the cost of medical devices.

Quality and Regulatory Concerns: ABS from new suppliers will need to be qualified to ensure that safety and effectiveness have not been impacted. 

Innovation Pressure: This situation may accelerate the exploration of alternative materials to reduce dependency on traditional ABS.

Specific Healthcare Manufacturing Aspects

1. Drug Delivery Systems. Impact: Potential redesign of portable drug delivery devices and auto-injectors
2. Diagnostic Equipment. Impact: Possible delays in production of imaging machine housings and laboratory instruments
3. Respiratory Care. Impact: Potential shortages of components for ventilators and other respiratory devices
4. Surgical Instruments. Impact: Possible delays in production of certain non-absorbable sutures and prostheses

In each of these areas, the challenge will be maintaining biocompatibility and device specifications with new materials.

Regulatory Challenges

Qualifying new ABS suppliers involves navigating complex regulatory pathways, which vary based on the device's risk classification. For 510K cleared devices, a supplier change can be documented with a letter to file that confirms verification with the new material or, if the new material impacts safety or effectiveness, in a new 510(k) submission.  For PMA cleared devices, a supplier change can be documented in the annual report or, if the new material impacts safety or device effectiveness, in a PMA supplement.  

How CPG Can Help

CPG can assist medical device manufacturers in developing a tailored regulatory strategy for qualifying new ABS suppliers. This strategy will consider:

1. Supplier Qualification Process: Developing criteria for selecting and evaluating new ABS suppliers based on FDA expectations, as well as REACH, RoHS, Prop-65, and MDR compliance.
2. Testing Protocol Development: Designing and implementing necessary tests to qualify ABS to ensure safety and effectiveness of the device have not been impacted. 
3. Regulatory Documentation Preparation: Assistance in preparing documentation that support the continued safety and effectiveness of the device, including biological risks assessments, memos, and letters to file. If necessary due to a change in safety or effectiveness, CPG can also assist in the preparation of new 510(k) submissions and PMA supplements.

By leveraging CPG's services, medical device manufacturers can navigate this supply chain challenge efficiently, minimizing disruptions to their production and market access while maintaining regulatory compliance. Collaboration between manufacturers, regulators, and material scientists will be crucial to maintain the quality and availability of essential medical products.

Holiday Hours

Please note that our lab will be closed on the following dates to allow our team to enjoy the holidays:

• December 24 - 25 (Christmas Eve & Day)
• December 31 - January 1 (New Year's Eve & Day)

We will resume normal business hours on January 2nd, ready to tackle your new materials challenges in the coming year.

If you have any questions or need assistance on existing quotes or projects, feel free to reach out by email or contacting us at 617-629-4400.

Additionally, if you have any new consulting or testing needs, we would be happy to discuss how we can assist you.

We are truly grateful for your partnership and look forward to providing you with game-changing material science consulting and testing in 2025 and beyond.

Warmly,

The Cambridge Polymer Group Team

ASTM recently published a new version of F2459 "Standard Test Method for Extracting Residue from Medical Components and Quantifying via Gravimetric Analysis.” This updated standard expands its scope beyond metallic implants to include ceramic and polymeric medical devices.

Key Updates and Applications

• Expanded Scope: The standard now covers residue assessment for metallic, ceramic, and polymeric medical devices.
• Cleanliness Assessment: It serves as a high-level evaluation method for medical device cleanliness.
• Additive Manufacturing: The standard provides a basis for preparing extracts for particulate residue assessment in additive manufacturing standards.
• FDA Recognition: The FDA recognizes this standard for quality assessment of medical device manufacturing facilities.

Significance and Contributions

• The standard identifies two techniques to quantify extractable residue on medical components.
• It allows investigators to compare relative levels of component cleanliness.
• The method's applicability has been demonstrated through numerous literature reports.

Impact on the Medical Device Industry

The expansion of ASTM F2459 to include ceramic and polymeric medical devices is a significant development for the industry. As medical technology advances, the materials used in device manufacturing have diversified, necessitating more comprehensive testing methods. This update ensures that a wider range of medical devices can be assessed for cleanliness using a standardized approach. 

Benefits for Manufacturers

1. Consistency: Provides a uniform method for cleanliness assessment across different material types.
2. Quality Assurance: Helps manufacturers maintain high standards of cleanliness in their production processes.
3. Regulatory Compliance: Aligns with FDA expectations, potentially streamlining the approval process.

Implications for Patient Safety

The enhanced standard contributes to patient safety by:

• Ensuring more thorough cleanliness assessments for a broader range of medical devices.
• Reducing the risk of contamination-related complications in patients.
• Promoting confidence in the safety and quality of medical devices.

The Role of Gravimetric Analysis

Gravimetric analysis, the core technique in ASTM F2459, involves precise weighing of residues extracted from medical components. This method:

• Provides quantitative data on the amount of extractable residue.
• Is highly sensitive, capable of detecting minute amounts of contaminants.
• Offers reproducible results, crucial for quality control and regulatory compliance.

Future Directions

As the medical device industry continues to evolve, particularly with the rise of additive manufacturing and novel biomaterials, standards like ASTM F2459 will likely undergo further changes. Areas of potential future development include:

• Integration with other analytical techniques for more comprehensive residue characterization.
• Adaptation to emerging manufacturing technologies and materials.
• Enhanced protocols for specific types of medical devices or materials.

Scientists from Cambridge Polymer Group contributed to the revisions of this standard and regularly conduct this test. Our involvement underscores the collaborative nature of standards development, bringing together expertise from industry, academia, and regulatory bodies.

This update reflects the evolving needs of the medical device industry, particularly in light of new manufacturing technologies like additive manufacturing. As the industry continues to innovate, the importance of robust, adaptable standards like ASTM F2459 becomes increasingly critical in ensuring the safety and efficacy of medical devices.

Polymer deformulation typically involves multiple tests to identify the type of polymer, assess the presence of potential blended polymers, and evaluate the incorporation of additives such as colorants, stabilizers, and processing aids. An elegant and more rapid alternative involves a form of pyrolysis gas chromatography mass spectrometry.

During pyrolysis, polymeric materials are rapidly heated to above their thermal decomposition temperatures such that covalent bonds are broken and rearranged. The resultant smaller fragments (pyrolyzates) are then separated using gas chromatography-mass spectrometry (GC-MS). Through identification of the pyrolyzates, the original polymer can be identified.

Challenges in Polymer Identification

Often, the pyrogram of a pyrolyzed polymeric material will contain peaks that do not originate from the polymer itself but instead can be traced back to:

• Volatile or semi-volatile residual solvents
• Monomers
• Contaminants
• Additives

These additional peaks can make accurate identification of the base resin more challenging and, likewise, identification of these peaks can be complicated by interference from the pyrolyzates. Although these compounds can be removed by an extraction process prior to pyrolysis GC-MS to separately characterize the volatile/semi-volatile compounds and identify the polymer, this approach can be unnecessarily burdensome.

Multi-Step Pyrolysis GC-MS

As an alternative approach towards characterization of both additives and the base resin, polymers can be subjected to multi-step pyrolysis GC-MS. Materials are initially heated to a temperature below the thermal decomposition temperature that allows for volatile and semi-volatile compounds to be thermally desorbed prior to pyrolysis. These compounds can then be identified and evaluated separately from the pyrolyzates of the base resin. The identity of the base resin can then be determined by heating the same sample to a temperature above the decomposition temperature. In sum, multi-step pyrolysis GC-MS can be used to evaluate the additive package and base resin of a polymeric material with only a small sample and no preparation beyond transferring the material to a quartz pyrolysis tube.

As an example of the utility of multi-step pyrolysis GC-MS, polypropylene often contains antistatic agents, slip agents, sterically hindered phenol antioxidants, and UV-absorbers. These compounds could potentially be obscured by the pyrogram that is typically associated with polypropylene pyrolysis. However, by using the multi-step approach, many of the contaminants, antioxidants, and UV-absorbers can be identified prior to pyrolysis. As shown below, thermal desorption of polypropylene at 350 °C yielded a sterically hindered phenol antioxidant, as well as a hexaethylene glycol, which likely is a functional group of a higher molecular weight slip additive. Pyrolysis of the same sample at 800 °C yielded a pattern of 1-alkenes consistent with polypropylene.  

On November 6, 2024, the FDA held a workshop to discuss the potential expansion of the Accreditation Scheme for Conformity Assessment (ASCA) program to include chemical characterization per ISO 10993-18. This expansion would build upon the current ASCA program, which primarily covers select biological endpoint tests according to ISO 10993. Because the FDA has already reviewed and approved the test methods by accredited laboratories, the ASCA program is intended to reduce additional information (AI) requests and FDA reviewer time.

Morning Session

• Industry stakeholders spoke about extractables and leachables (E/L) testing approaches.
• Discussion focused on proficiency testing and the coverage map provided by surrogate compounds.
• FDA shared results from a recent round robin E/L study involving eight laboratories.

Afternoon Session

• Focused on the potential scope of an expanded ASCA program.
• Outlined proposed accreditation process for laboratories.

Proposed ASCA Accreditation Process

1. External accreditation to ISO 10993-18, such as ISO 17025
2. Submission of E/L testing protocols to FDA, including:

• Extraction procedures
• Equipment setup and verification
• Sample testing
• Data analysis

3. Provision of personnel training evidence

If the FDA accredits a laboratory, reports can be summaries of procedures and results, with less FDA scrutiny. Challenging devices (e.g., hydrogels, degradables) that may require unique testing methods would fall outside of the ASCA accreditation program.

Key Discussion Points

The FDA sought input on various aspects of ISO 10993-18 testing, including:

• Test article preparation methods
• Use of response factor databases
• Selection of surrogate compounds for semi-quantitation
• Identification confidence criteria

Attendees, including Dr. Becky Bader and Dr. Stephen Spiegelberg from Cambridge Polymer Group, participated in the Q&A session and plan to provide additional written feedback.

Next Steps

The FDA will review workshop discussions and subsequent written feedback as they consider the potential expansion of the ASCA program. The agency will post responses to the questions raised during the workshop as they continue to evaluate this expansion.

This workshop represents another step in the ongoing dialogue between the FDA and industry stakeholders regarding chemical characterization testing for medical devices. The potential expansion of the ASCA program could have significant implications for both testing laboratories and device manufacturers.