Recent ISO Standards Highlight Global Submission Complexities

Submitting a medical device for regulatory approval is typically a long and laborious process—and rightfully so. A device’s classification, the primary mode of action, relevant regulatory standards, and testing requirements determine the submission requirements specific to each product. Evolving regulatory requirements and standards mean manufacturers can anticipate regulatory delays, timeline shifts and fixed project milestones. When preparing to submit a medical device to multiple regulatory bodies around the world, the number of factors to consider can be downright daunting.

Despite their challenges, global submissions may be ideal for manufacturers on several fronts. Access to international markets means bringing life-changing medical devices to a significant number of patients internationally, in addition to a financial windfall. However, submitting to multiple regulatory bodies means ensuring a medical device adheres to each regulatory body’s requirements and interpretation of standards from the International Organization of Standards (ISO).

The language used in regulatory standards can be vague and subject to interpretation. A common practice in one region may not be recognized in others so manufacturers should be aware of the governing body’s interpretations. Additionally, interpretations evolve as regulators receive additional data when reviewing submissions. Staying informed about the guidance coming from each regulatory body is critical to ensuring medical device submissions are aligned accordingly.

Two recent ISO standards—10993-18 Chemical characterization of medical device materials within a risk management process (revised in 2020) and 10993-23 Tests for irritation (published in 2021)—demonstrate how understanding a regulatory body’s interpretation can be paramount to a successful regulatory submission. 

An Overview of ISO 10993-18 and 10993-23
ISO revised 10993-1 Evaluation and testing within a risk management process in 2018 and, in doing so, set the standard for biological evaluation and understanding of a medical device’s physical and chemical evaluation. In 2020, ISO revised 10993-18 to bring additional clarity to the expectations around chemical characterization. The standards also introduced the analytical evaluation threshold (AET), the level at which chemicals extracted from a medical device must be identified and quantified for toxicological risk assessment.

When ISO published 10993-23 in January 2021, it marked a paradigm shift for in-vitro testing alternatives. The standard evolved from a European validation study that used a skin irritation assay as part of a cosmetic directive. Two valuable characteristics of ISO 10993-23’s assay include (1) that it tests two types of reconstructed human epidermis (RhE), and (2) it can detect irritant chemicals extracted from medical device materials. For years, scientists and regulators anticipated ISO 10993-23 because it promised to reduce, refine, and replace in-vivo test methods to assess skin irritation.

ISO 10993-23 represents a split from ISO 10993-10 Tests for irritation and skin sensitization. ISO 10993-10 still contains language on skin irritation but will eventually cover only sensitization. For the moment, two standards exist to evaluate the irritant potential in medical devices.

U.S. Food and Drug Administration
The U.S. Food and Drug Administration’s (FDA) Center for Devices and Radiological Health (CDRH) regulates firms that manufacture, repackage, relabel, or import medical devices sold in the United States. The regulatory body classifies medical devices into three classes, with regulatory control increasing from Class I to Class III. A device’s class determines, among other factors, the type of regulatory submission required.

• ISO 10993-18: The FDA recognized ISO 10993-18:2020 in July 2020 but stopped short of full recognition. That said, the regulatory body still expects complete chemical characterization data and a toxicological risk assessment for almost all medical devices submitted. Manufacturers should be aware that the intensive chemistry requirements create massive data sets that must be assessed for biological safety. Planning additional time for chemical characterization should be part of any submission strategy.
• ISO 10993-23: The FDA partially recognizes ISO 10993-23 on its “scientific and technical merit” and because it supports existing regulatory practices vis-à-vis the three Rs. The regulatory body was instrumental in drafting the standard but didn’t fully recognize it due to conflicts with published guidance.

EU MDR
The arrival of the EU’s Medical Device Regulation (MDR) in May 2021 set a new precedent for medical device manufacturing and approval in Europe. The regulation changed how devices are classified in the EU and introduced strict requirements that prioritize patient safety.

• ISO 10993-18: Medical devices submitted in the EU should include chemical characterization information that complies with ISO 10993-18. The EU has not harmonized the standard across all member states, but regulators consider it state-of-the-art as the latest accepted version. MDR also empowers notified bodies to interpret the meaning of “state-of-the-art” and work with manufacturers to ensure compliance with standards before submission. While rigorous chemistry is now commonplace for medical devices submitted in the EU, manufacturers should also plan for significant backlogs during EU submissions. The number of accredited notified bodies dropped from 125 to around 20 as MDR became effective.
• ISO 10993-23: ISO 10993-23 is considered state-of-the-art, and the EU harmonized it across all member states in July. Notified bodies prefer a risk-based approach and alternatives to replace in-vivo testing. Regulators will consider chemical characterization data, previous testing, published literature, in-vitro test results, and a safe clinical history when approving or denying submissions. In-vitro irritation testing is expected, unless the irritation cannot be evaluated by other methods, including chemical characterization, risk assessment or in-vitro testing. With justification, the in-vivo test may be necessary.

PMDA & MHLW (Japan)
The Pharmaceutical and Medical Device Agency (PMDA) and the Ministry of Health, Labor, and Welfare (MHLW) regulate pharmaceutical and medical devices in Japan. The PMDA works with the MHLW to assess medical device safety and effectiveness. Japan uses a risk-based classification system to categorize medical devices into four classes based on associated risk with Class I representing the lowest potential risk; and Class IV representing the highest potential risk. Marketing medical devices in Japan requires separate registration through the MHLW, but EU or U.S. FDA approval can help streamline submissions.

• ISO 10993-18: In February 2020, Japan published Notification No. 1006-1, recommending medical device manufacturers use the most recent version of ISO 10993 standards, with expanded expectations for biological evaluations. Most of the expectations are consistent with ISO standards, including the endpoints for evaluation listed in ISO 10993-1:2018.
  
  Furthermore, all biocompatibility tests in Japan must comply with Good Laboratory Practices. Japanese regulators also expect detailed information on physical and chemical data, raw materials used in the device, manufacturing and sterilization methods, design, physical features, and human body contact. The MHLW also conducts a data integrity review to confirm data reliability, and it may also request raw data for any biocompatibility test conducted. 

• ISO 10993-23: In-vitro irritation testing using RhE was already included in MHLW guidance before ISO published 10993-23. The MHLW requires manufacturers to perform in-vitro irritation tests specific to the route—i.e., skin, eye, mucosal region—and duration of exposure or contact.

NMPA (China)
The National Medical Products Administration (NMPA) creates, supervises, and implements policies and standards governing medical devices, cosmetics, and drugs in China. The agency also oversees registering and inspecting similar products.

The NMPA recently adopted a progressive regulatory philosophy with the passage of its Medical Device Regulations (State Council Order #739) in June 2021. One of China’s new national priorities is medical device innovation. As such, medical devices treating rare or unmet need diseases can apply for conditional approval and may find their submissions fast-tracked. Likewise, the NMPA will waive clinical evaluation for mature products and those for which safety and effectiveness can be proven by means other than clinical evaluation. The NMPA will also allow clinical study data or analysis of clinical literature and clinical data on predicate devices to demonstrate product safety and effectiveness.

Similar to how notified bodies operate in the EU, medical device manufacturers must appoint a Chinese legal entity to submit regulatory applications, correspond with regulatory authorities, and ensure statutory compliance. Each device submission is subject to the reviewer’s discretion. Device manufacturers must also submit samples for all submissions and translate product information, packaging, labels, etc., into simplified Chinese.

• ISO 10993-18: Although the NMPA does not universally accept current versions of ISO standards, it may accept ISO standards that have undergone a conformity assessment and adhere to current Chinese Guobiao (GB) standards. Biocompatibility evaluations must reference the GB and corresponding ISO standard. Medical devices already holding EU approval or 510(k) clearance from the U.S. FDA are granted alternative—and historically faster—submission processes.
• ISO 10993-23: China contributed to the research used to evaluate the RhE model in assessing skin irritation. Accepted industry standards (i.e., norms) are abbreviated with “YY” and define the scope, parameters, and prescriptive limits for medical products seeking approval in China. The NMPA uses the YY designation when no corresponding GB standard exists. Manufacturers may encounter a delay when submitting using ISO 10993-23 until the NMPA publishes the YY version.

Bottom Line on Global Submissions
While global bodies like ISO create and update standards continuously, regulatory bodies in each country or region may interpret the standards differently and, in turn, provide published guidance for specific markets. Whether a device is submitted for approval in the United States, EU, Japan, or China, manufacturers can anticipate complex, culturally nuanced, and sometimes incomplete guidance.

Understanding and staying current with each agency’s interpretation of standards is a challenging and time-consuming endeavor—especially if manufacturers try to do it alone. Enlisting an experienced laboratory partner to develop a regulatory submission strategy will help achieve regional compliance to get medical devices everywhere they need to be.

The challenges inherent in global submissions should not dissuade manufacturers. The financial and healthcare opportunities in delivering products to multiple markets often outweigh the hurdles they may face. The regulatory landscape is ever-evolving to ensure the medical device industry prioritizes patient safety. Manufacturers who take extra care when setting project expectations and establishing timelines can better navigate global submissions. 

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Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).

Dr. Sherry Parker has more than 20 years of toxicology and medical device experience, and is an expert in biological evaluation of medical devices and combination products. She received her Ph.D. in molecular and cellular pharmacology from the University of Miami. In her current position as WuXi AppTec’s senior director of Regulatory Toxicology, Dr. Parker provides manufacturers guidance on global regulatory and technical requirements, and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Biological Evaluation (AAMI/BE) Committee, the U.S. mirror committee for ISO 10993. In addition, she is currently an internationally recognized ISO expert and a U.S. Delegate for TC 194, the technical committee for ISO 10993, and is a past president of the Medical Device and Combination Products Specialty Section of the Society of Toxicology.

Mark Cabonce, M.S., DABT, serves as a principal toxicologist at WuXi AppTec with a focus on medical devices and combination products. Before joining WuXi AppTec, he served as a toxicologist managing regulated in vivo and in-vitro acute toxicology studies, assessing formulation dossiers for GHS classification and labeling, and preparing risk assessment in support of domestic and international product registrations. He also managed pharmaco-kinetic and preclinical safety evaluation studies for a broad range of pharmaceutical and agrichemical clients under prevailing U.S. EPA, FDA, and OECD guidelines. He earned a M.Sc. degree in biology from St. Louis University, and has been a diplomat of the American Board of Toxicology since 2005.