Combination products—as the name suggests—represent a mixture of medical products. They comprise any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product.
The variety of possible combinations make them a difficult product category to usher through the regulatory process, and device manufacturers can quickly find themselves lost in a complicated and ever-changing undertaking.
In this post we’ll examine how to make the regulatory route for combination products easier to navigate and cut down on the time and cost required to bring them to market.
What are examples of combination products?
There are three different types of combination products. Some are single entity, where the components are combined, such as a monoclonal antibody combined with a therapeutic drug, or a device coated or impregnated with a drug or biologic. Prefilled drug delivery systems, like syringes, insulin injector pens and metered dose inhalers, are included in this category of combination product.
The second group is co-packaged combination products such as a drug or vaccine vial packaged with a delivery device, or first aid kits containing devices (like bandages or gauze) and drugs (such as antibiotic ointments or pain relievers).
Finally, there are cross-labeled combination products, where components are provided separately but specifically labeled to be used together. A photosensitizing drug and an activating light source (i.e., laser) is a good example of this category of combination product.
Who regulates combination products?
In the United States, the U.S. FDA regulates combination products, but manufacturers need to work with a specific center within the agency, depending on the nature of the product they want to take to market.
The Office of Combination Products (OCP) is the starting point. OCP is the focal point for combination product issues and medical product classification. It also develops the guidance to clarify the regulation of combination products.
After OCP, drug and device manufacturers must submit to different FDA centers depending on the type of combination product. The Center for Drug Evaluation and Research (CDER) focuses on drug-related products, the Center for Devices and Radiological Health (CDRH) reviews medical device products, and the Center for Biologics Evaluation and Research (CBER) assesses biological products. Each of these centers have different expectations and requirements, which makes submitting a combination product for review potentially complex.
Ensuring a successful submission
1. Start Early and Establish Primary Mode of Action
It is vital that manufacturers start early when submitting a combination device for regulatory review. This means establishing a plan of action well ahead of time to meet deadlines. The first step in the process is to determine a product’s primary mode of action (PMOA). The U.S. FDA defines the PMOA as the single mode of action that provides the most important therapeutic action of the combination product.
The PMOA dictates which of the U.S. FDA centers a manufacturer must approach first. Defining the PMOA in a combination product requires a manufacturer to look closely at how a drug or device interact with each other.
If the device is the primary mode of action, the manufacturer should submit to the CDRH for initial review. CDER would be the first point of contact for a company with a combination product in which the drug is the PMOA. Device manufacturers of biological products should consult first with CBER.
If a device has two independent modes of action and neither can be described as subordinate to the other, the U.S. FDA uses an algorithm to determine center assignment.
This is arguably the most important step in the process. The correct lab testing partner can navigate the tricky waters of a combination product submission and guide a manufacturer through any unexpected twists and turns.
2. Select an experienced lab testing partner
Manufacturers also need a lab testing partner with firsthand knowledge of the current regulatory environment, which can evolve or change over time. Regulators’ expectations are both complex and dynamic. An experienced lab partner is continuously engaged with regulators throughout the world, which can help inform and quicken the entire process.
Finally, lab partners provide the expertise (through their equipment, credentials, and databases) to meet new requirements and expectations, such as complete chemical characterization of medical devices or compound elucidation of drug components. There just isn’t a great substitute for lab partners who understand the regulatory environment and have the capacity and capability to guide a new product toward submission.
3. Request a pre-submission meeting
Manufacturers can save a lot of time and effort if they request a pre-submission meeting with the U.S. FDA. Pre-submission meetings are informal opportunities to receive feedback or answer agency questions while preparing products for submission. They are also invaluable in understanding regulators’ expectations. They really help establish the most efficient route to regulatory success for combination products. Also, lab testing partners can help prepare, and even participate in, such meetings.
The bottom line
The regulatory route for a combination product can easily become a maze for manufacturers with little experience or assistance. Establishing the right U.S. FDA center to submit to can be challenging, especially given a combination products’ PMOA is sometimes unclear.
Selecting the right lab testing partner with ample expertise, deep knowledge about regulations, and experience dealing with combination products can make the entire process much more straightforward.
Not all plastics are created equal. Plastic and polymeric products, parts and components can include significant numbers of chemical constituents—so it is important to understand how a filter, bag, container, delivery system or implantable device will react while in use. Complete chemical characterization is necessary to determine what compounds are present and how these compounds may impact patients.
Many chemicals present in plastic and polymer products are expected, but some are unexpected—and potentially harmful. Extractables/leachables (E/L) testing is the most effective way to identify and quantify all compounds within a delivery system, container or other test article. E/L testing comprises two kinds of testing to identify chemical constituents in a medical device.
- Extractables testing: Generates “worst-case” data and ascertains how plastics and polymers react to exaggerated conditions (range of solvent polarities, high temperatures, extended time frames, etc.).
- Leachables or Simulated-Use Extractables testing: Assesses what chemical compounds may migrate from a plastic or polymer during “normal” or clinically relevant conditions. Often, testing deemed “clinically relevant” is simulated due to the challenges of working with actual biological matrices.
Even common materials or those with a long history of clinical use can contain chemicals of concern—and regulatory bodies are taking notice. Per ISO 10993-1, most medical devices require extractables studies and a toxicological risk assessment, with potentially additional chemistry (e.g., leachables or simulated-use extractables) to mitigate risks and address biocompatibility endpoints.
Caution is Key
Polypropylene has been approved by the U.S. FDA for use in more than 170 health care products—sutures, surgical mesh, cardiovascular patches, packaging and single-use systems, to name a few—but the material is not implicitly safe in all use cases. Analytical chemist Dennis Jenke identified 35 extractables associated with polypropylene materials, some of which can present a toxicological concern even at very low levels. Take benzopyrene, for instance: Though frequently used in polypropylene production, benzopyrene can cause cell mutations and lead to various forms of cancer in addition to developmental toxicity.
Clinical use case also matters. Recently, the U.S. FDA identified a potential risk of exposure to toxic chemicals associated with silicone tubing in three models of a major manufacturers’ hemodialysis machines, all of which were introduced in 2008. Two of the models are no longer manufactured but remain in clinical use. Given the role these machines play in purifying patients’ blood, any level of toxicity could pose significant safety risks.
Comprehensive E/L studies can identify and help mitigate risks before potentially harmful chemical compounds impact patient safety. To do so, manufacturers need to embrace testing as a journey of discovery rather than a one-and-done affair.
Vet Your Lab Testing Partner
Not every laboratory testing partner is capable of complete chemical characterization with no unknowns, and the level of vigor in E/L testing can vary. Ask the right questions early in the process to prevent surprises down the road. Helpful questions include:
- How long has the laboratory been conducting E/L studies? How many programs have you run?
- Can you commit to the elucidation and complete identification of all components?
- Is complete identification included in price and timeline quotes, or does this incur an additional charge? What is your on-time delivery record and when does that clock start?
- What support do you provide after analytical testing concludes? Is the testing team available to address regulator questions?
Some laboratories may claim to offer E/L testing but fail to deliver complete chemical characterization when the process becomes complex or time consuming. Asking the right questions when vetting partners allows manufacturers to make informed decisions, streamline the testing process and market safe products.
A Final Word on E/L Testing Just because a plastic or polymer has been used before does not mean that manufacturers can assume it safe for a specific application or use case. Complete E/L testing identifies all chemicals present within a product. When unknowns are present, it is virtually impossible for the toxicologist to assess the device’s toxicological risk accurately; and unidentified chemicals must be considered carcinogenic or genotoxic. Savvy manufacturers will question every unknown compound related to their container, delivery system, or product—because they know regulators will flag them. Lab testing partners who fail to identify all compounds or attempt to proceed with unknowns present should be equally scrutinized.
The most rewarding part of the job for medical device manufacturers is seeing the result of their hard work making a real difference in patients’ lives. But getting an effective, innovative, and safe product to market in the U.S. and the European Union (EU) means navigating a series of regulatory hurdles. One blog post in a two-part series, we will look at the best way to achieve that goal in the U.S.
The regulatory difficulties of bringing a medical device to market are almost as complex as the process itself. The U.S. Food and Drug Administration (FDA) regulates the manufacturing and use of medical devices and has done so since the passing of the 1938 U.S. Food, Drug & Cosmetics Act. Over the decades, the U.S. FDA’s approach to this regulation has changed, and today the agency adopts a risk-based approach to medical devices.
Specificity matters in the regulatory process
The U.S. FDA has classified around 1,700 medical devices to date, sorting them into 16 specialty areas—also called panels—and then organizing them into the Code of Federal Regulations (CFR). The classification considers the intended use of the device and its indications for use. That’s not quite as simple as it sounds.
For example, a scalpel is used to cut tissue, so its intended use is reasonably clear-cut. But its indication for use (most often found in the device’s label) can be much more specialized. A scalpel that cuts delicate corneal tissue will include a different indication than one designed to slice through thicker dermal tissue. The different indications can impact the device’s classification.
Classification of risk
Risk is an essential part of the classification process. Devices are sorted into groups based on their perceived risk to a patient. Class I devices pose the lowest risk, while Class III devices pose the highest potential risks. This classification determines the device’s route to regulatory clearance.
Most Class II medical devices obtain regulatory clearance through a premarket notification (i.e., a 510(k) submission). This submission must show that the device is substantially equivalent (SE) to a device with an identical intended use already cleared for sale in the United States. Due to their perceived low level of risk, most Class I devices are exempt from premarket notification 510(k).
For Class III devices, a 501(k) isn’t enough—they often require premarket approval (PMA). A PMA is an application that documents the device’s safety and effectiveness. The application consists of three sections—technical, non-clinical lab studies and clinical investigations—designed to demonstrate sound scientific analysis and reasoning around the device. The PMA process is intricate, and around 20% of manufacturers are required to include clinical data in their PMA submissions. If a Class III device doesn’t meet PMA requirements, it cannot be marketed.
Moreover, PMAs that are incomplete, inaccurate or omit critical information may be delayed or rejected outright. Manufacturers are encouraged to audit any PMA applications for consistency, accuracy and scientific soundness before submitting it to the U.S FDA.
Finding an equivalent medical device
Whenever possible, manufacturers should choose one of their own medical devices as the predicate.
They can provide details of manufacturing sites, processes, processing aids, and quality controls that aid in establishing equivalence. This level of detail would not otherwise be available if they were to select a competitor’s product as the predicate device. If a competitor’s product is selected, manufacturers would do well to choose one that has recently been cleared under 510(k) guidelines.
But what makes a device substantially equivalent? The U.S. FDA wants something that has:
- An identical intended use to the predicate; and
- Identical technological characteristics to the predicate; or
- An identical intended use to the predicate; and
- Different technological characteristics but has the same safety and effectiveness assurances; and
- Information submitted to FDA demonstrates the device is as safe and effective as a legally marketed device.
Manufacturers cannot distribute devices requiring a 510(k) submission until they receive a letter of SE from the FDA, which acknowledges that the device is as safe and effective as the predicate.
The process gets a little trickier if the device is novel and has no predicate. If the device has a Class I or Class II risk level, manufacturers can apply for a “De Novo” request. The U.S. FDA advises submitting a De Novo application and a pre-submission evaluation so the regulators can provide feedback or guidance before the next stage: official premarket submission.
Alternative paths to regulatory approval
The U.S. FDA has demonstrated a willingness to grant emergency use authorization (EUA) to new medical devices designed to help the fight against SARS-CoV-2 (i.e., COVID-19). EUAs extend beyond that one disease and can allow the U.S. FDA to authorize unapproved devices or unapproved uses of devices in other emergencies.
Class III medical devices that treat rare diseases or conditions can also take a less stringent path to market. Manufacturers can apply for humanitarian use designation (HUD) through the FDA’s Office of Orphan Products Development (OPD). The definition of rare in this case refers to diseases or conditions that affect no more than 8,000 individuals in the U.S.
Combination products, which contain a mix of drugs, devices and biologics, require an alternative path through the regulatory system. One of three different regulatory centers may oversee combination products’ pathways, but that determination comes down to the device’s primary mode of action. The complexity of these devices requires additional guidance from the U.S. FDA’s Office of Combination Products.
Final advice for navigating the regulatory system
The above guidance simplifies what can be a very complex process. To streamline the submission process for devices bound for the U.S. market, U.S. FDA regulators encourage manufacturers to take a more active and collaborative approach to their submissions. Part of this effort includes scheduling a pre-submission meeting with regulators to discuss the device, review testing strategies and connect with the experts on your team. Doing so can help save time and money long-term by garnering nonbinding regulatory insight on the road to a successful submission in the U.S. But the whole process can be daunting and time-consuming, especially for device manufacturers new to the U.S. market or those looking to gain regulatory clearance or approval for novel or humanitarian devices. Missing one small step in the process can cause a giant setback, so using an experienced laboratory testing partner can improve manufacturers’ chances of a smooth journey through the regulatory process.
Complete chemical characterization is critical for not only the submission of your medical device but also – and most importantly – patient safety. This primer covers the most important things you need to know about performing a complete chemical characterization under ISO 10993-18.
ISO 10993 is a series of standards published by the International Organization for Standardization (ISO) that covers the process for evaluating the biocompatibility of medical devices to manage biological risk. Chemical characterization is the first step of the biological evaluation process, but it’s covered by Part 18 of the series.
Regulatory expectations for medical devices are higher than ever, and interpretations are in flux. ISO 10993-1, which sets the stage for the rest of the series, was updated in 2018 with an increased emphasis on chemical characterization. ISO 10993-18 was then updated in 2020 to reflect new expectations for replicates, intensified extractions and the analytical evaluation threshold (AET) – all to drive more robust toxicological risk assessments (which are covered in ISO 10993-17).
Simply put, there’s a lot to unpack. Here’s what manufacturers need to know about ISO 10993-18.
What is ISO 10993-18?
The official title: ISO 10993-18:2020: “Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process”
As a recap from ISO 10993-1, there are generally three critical elements evaluating biological risks:
- Complete chemical characterization
- Toxicological risk assessment
- Biocompatibility testing
Chemical characterization is the starting point that feeds into toxicological risk assessments, as the combination of these two steps often addresses several biocompatibility endpoints. Biocompatibility testing should be used to help meet the necessary endpoints that cannot or could not be addressed in the chemistry and risk assessment.
Part 18, provides specific guidance on chemical characterization testing requirements and exposure dose estimation, ultimately helping the chemist gather the information necessary to design a study that will be appropriate for the toxicological risk assessment.
Why is ISO 10993-18 (and Chemical Characterization) Important?
Hazardous chemicals may be introduced into a medical device during routine activity such as manufacturing, sterilization, and storage as well as impurities in the raw materials. The purpose of ISO 10993-18 – and the goal of chemical characterization – is to identify all of the chemical constituents in a medical device so that those chemicals can be assessed as part of a toxicological risk assessment.
The data collected from chemical characterization helps toxicologists calculate the potential risk to patients. To effectively do this, it’s critical to identify all chemicals present above the analytical threshold that is determined in partnership between chemistry experts and toxicologists, with justification of the AET expected by regulatory bodies. This is one of the key reasons why ISO 10993-18 introduced the AET in the 2020 update, better aligning the work of chemists and toxicologists when designing studies. In short, the AET sets the baseline at which chemicals should be identified, reported, and evaluated for potential toxicological concern in the risk assessment.
When chemicals are left unidentified, they must be considered carcinogenic or genotoxic, and toxicologists won’t be able to accurately assess the medical device’s toxicological risk. Thus, the more unknowns a device has, the more likely it is to face additional scrutiny from regulators.
When Should Medical Device Manufacturers Consider ISO 10993-18?
As mentioned, chemical characterization of a medical device is the first step in the biological evaluation process, which means you should care about ISO 10993-18 early on in the preclinical testing process. But it must be completed on the finished medical device as part of the regulatory submission package. This gives chemists and toxicologists the full picture, including manufacturing and sterilization methods that might impact the extractables profile of the product.
Bottom line: Chemical characterization should be considered a journey, not a check-box exercise.
How Do Regulatory Authorities Approach ISO 10993-18?
Regulatory bodies in the US and EU have incrementally interpreted, adopted, and implemented ISO 10993-18:2020.
The U.S. Food and Drug Administration (FDA)
While the FDA stopped short of full recognition, it does expect manufacturers submitting products for use in the U.S. to address the requirements of the standard.
The FDA accepts most of ISO 10993-18:2020, with a few notable exceptions related to:
- Applying the limit of quantification (LOQ) when the AET is unachievable.
- Grouping chemicals into classes to assist with toxicological risk assessment.
- Selecting surrogate extraction vehicles correlating chemical to biological testing.
- Issues related to determination of uncertainty factors in the AET calculation.
The FDA argues that the portions of the standard that are not recognized are in conflict with published literature or other recognized standards, or include technical errors that will be corrected in subsequent versions of the standard.
As acknowledged in their guidance document on the use of ISO 10993-1, published in September of 2020, the FDA clearly recognizes the importance of chemical characterization as part of an overall biocompatibility evaluation and that characterization data may be used to address several biocompatibility endpoints (e.g., genotoxicity, carcinogenicity, developmental toxicity). As a general rule, the FDA expects the chemical characterization studies to be conducted in accordance with ISO 10993-18:2020, especially with respect to solvent selection, extraction conditions, and inclusion of the AET.
The EU Medical Device Regulation (MDR)
In 2021, the MDR provided a new, more comprehensive regulatory framework for medical devices, changing how devices are classified and introducing stringent requirements that prioritize patient risk.
When it comes to ISO 10993-18:2020, the MDR has accepted the standard as “state of the art” and generally holds manufacturers to it. However, the EU has yet to harmonize the standard across member states. It’s up to notified bodies to interpret the meaning of state of the art and work with medical device manufacturers to ensure a smooth submission process.
So, what does meeting regulatory expectations really look like, especially today when those expectations are higher than ever? It depends on where you plan to submit, but there are some general tips you can follow to set your product up for success.
What Do Medical Device Manufacturers Need to Do to Meet Regulatory Expectations?
To follow ISO 10993-18 and meet current FDA and/or MDR expectations, the key is planning and preparation. Taking a proactive approach to these requirements will help you prevent gaps in your information that may lead regulators to question your data and your methods. It is not out of the ordinary to have regulators request repeat testing, adding cost and timeline to your project.
Here are some key takeaways for meeting current regulatory expectations and a smoother path to regulatory clearance for your medical device:
#1. Stay Current with Regulatory Updates
It sounds obvious, but it can’t be understated: The best way to meet expectations is to stay current with regulatory updates.
Those that stress preparedness and ensure their chemical characterizations are conducted according to the current regulatory thinking have an advantage in the submission process. Be sure to carefully read recent regulatory updates and anticipate expected changes in other standards to avoid delays in the process.
One advantage of outsourcing your chemical characterization testing is to leverage the lab’s experience with similar products and their knowledge of regulators’ expectations. Labs that maintain a database of regulators questions will be valuable in addressing any requests for additional information.
#2. Provide Complete Chemical Characterization with No Unknowns
A chemical characterization report that includes unknowns will likely face additional regulatory scrutiny and may jeopardize your submission.
That’s why it’s critical to identify all chemicals associated with your device above the AET. However, identifying all compounds above a certain level depends on your testing lab’s capabilities and resources.
#3. Anticipate Risk-Mitigation
ISO 10993-18:2020 recommends more exaggerated and exhaustive chemical characterization conditions – and regulators expect them. Because of this, more chemicals are identified and the chances of having chemicals of concern increases.
So, medical device manufacturers should enter into these studies anticipating risk-mitigation, including:
- Simulated use extractables study
- Targeted study
- Additional biological testing
When you plan timelines, budget, and test articles for risk-mitigation, you won’t be thrown off if you do need to conduct additional testing.
Can Device Manufacturers Manage 10993-18 Testing In-House?
To move towards a successful submission, medical device manufacturers must complete:
- Preliminary chemistry testing
- Extractables/leachables (E/L) testing
- Toxicological risk assessment
- Risk mitigation, if necessary
It’s a lot to manage, but it can be done in-house or outsourced to a specialized lab.
Ultimately, outsourcing testing makes sense for some manufacturers but not for others. One of the main considerations you must weigh is whether the data generated from testing will be complete enough to meet regulators’ expectations.
Here are the pros of testing in-house:
- You own the medical device testing process and have control over the whole project, from technical insights and costs through timing and submission decisions.
- You don’t have to compete with other manufacturers for priority.
- You don’t have to deal with delays outside of your control.
If your manufacturing company does decide to test in-house, ensure that your internal team:
- Is aware of the latest testing standards and regulatory expectations.
- Has experience with E/L studies and elucidation.
- Has written risk assessments on medical device products before.
However, testing in-house is not always the best option, especially if you don’t already have infrastructure up and running. Building a facility, hiring expert chemists and toxicologists and purchasing highly sensitive lab equipment alone will take a lot of time and cost millions of dollars. A lot needs to happen before testing can even begin, so bringing it in-house may not be feasible.
So, what other options are available to a device manufacturer?
Working with a Medical Device Testing Partner for ISO 10993:18
Outsourcing testing to a specialized lab comes with a number of benefits that address the above challenges and more. Here’s what you can expect:
#1. Unbiased Evaluation
When analytical techniques are biased towards expected analytes, unexpected analytes could be missed in the evaluation. Using a third-party lab ensures that the analytical techniques are not biased toward expected analytes.
#2. Access to Experts to Identify More Compounds
You are the expert in your medical device, but identifying compounds requires an entirely different set of skills and knowledge. When you outsource to the right lab, you gain access to experts who are capable of complex elucidation to identify compounds and you have access to their chemical database.
Although commercially available libraries to help identify chemicals exist for gas chromatography, the LC-MS method does not have a commercially available library. Partnering with a lab dedicated to complete chemical characterization with no unknowns alleviates some of the burden of identification.
#3. More Visibility Into Regulatory Agencies
Specialized labs often have visibility into types of products, regulations, new standards, and questions or requests that may come from regulatory agencies. This visibility will help you address Additional Information (AIs) requests quickly. Also, the ability to anticipate questions helps with the initial design of studies to proactively address potential concerns.
Chemical characterizations and toxicological risk assessments require specific tools, methods, and expertise to know when and how to use different analytical methods. You wouldn’t want a general practitioner to attempt open-heart surgery. Specialization in the field of medical device testing works the same way.
WuXi AppTec has seasoned chemistry and toxicology experts that are well versed in E/L testing and identifying unknown chemicals. Over the past 11 years conducting E/L programs on medical devices, we have built an extensive LC-MS chemical database allowing our experts to leave no compound unidentified.
Talk to an expert about your upcoming project to see how we can help.
As a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable global pharmaceutical and healthcare industry to advance discoveries and deliver groundbreaking treatments to patients. Through its unique business models, WuXi AppTec’s integrated, end-to-end services include chemistry drug CRDMO (Contract Research, Development and Manufacturing Organization), biology discovery, preclinical testing and clinical research services, cell and gene therapies CTDMO (Contract Testing, Development and Manufacturing Organization), helping customers improve the productivity of advancing healthcare products through cost-effective and efficient solutions. WuXi AppTec received AA ESG rating from MSCI in 2021 and its open-access platform is enabling more than 5,850 collaborators from over 30 countries to improve the health of those in need – and to realize the vision that “every drug can be made and every disease can be treated.”