The annual Combination Products Summit focuses on solutions for the dynamic drug delivery/combination products industry with evolving regulations. Since 2015, it has united industry leaders and regulators to support innovation and navigate the complexities specific to the world of combination products. It’s hosted by the Association of Food and Drug Officials (AFDO) and Regulatory Affairs Professional Society (RAPS).

At last year’s Summit, the Office of Combination Products (OCP) at the U.S. Food and Drug Administration (FDA) discussed seven priority guidances in development. OCP director Thinh Nguyen hoped the guidelines would be published in the first quarter of this year, but at the time of writing they have not been released. They include:

• Human factors for combination products (final guidance)
• Essential performance requirements: established conditions and combination products (draft guidance)
• Technical considerations for demonstrating reliability of emergency-use injectors (final guidance)
• Combined use/cross-labeled combination products (draft guidance)
• Postmarket changes to combination products (draft guidance)
• Unique device identifiers and combination products (draft guidance)
• Labeling considerations for insulin pumps

Nguyen told Regulatory Focus (a RAPS publication) that the guidances were currently going through the review and clearance process in parallel, and it’s hard to pinpoint when they’ll be ready. He said OCP guidances must be cleared by multiple product centers, which tend to slow things down.

“The clearance process for combination products is going to be more complex than just a device or drug guidance because they just have to go through their center but now you have to go through three different centers,” Nguyen told Regulatory Focus. “It just takes more time.”

Because they contain both a pharmaceutical and device component, combination products present development, manufacturing, and regulatory challenges. This article seeks to examine these factors, with expert insights from those dealing with drug-device combination product manufacturing.

Market Forces for the Industry

Chronic disease, according to the Centers for Disease Control and Prevention (CDC), is one of the leading causes of death and disability in the U.S. According to CDC, six in 10 U.S. adults have a chronic disease, and four in 10 U.S. adults have two or more.¹ Chronic disease is also one of the leading drivers of the nation’s $4.1 trillion in annual healthcare costs.

“The rising incidence of chronic and degenerative diseases such as cancer, diabetes, eye-related, and cardiovascular diseases is driving demand for drug delivery technologies that can provide sustained release of medication,” said Meredith Canty, senior director of drug delivery for SMC Ltd., a Somerset, Wis.-based contract manufacturer for the medical, diagnostics and pharmaceutical markets. “This includes technologies such as autoinjectors, on-body devices, and implantable drug products that can deliver the appropriate dose to the patient.”

Drug delivery/combination product technologies have enabled development of many pharmaceutical products that improve health by enhancing delivery of a therapeutic to its target site. This minimizes off-target accumulation and assists with patient compliance.

Therapeutic modalities have grown beyond small molecules to include nucleic acids, peptides, proteins, and antibodies and drug delivery technologies were adapted to tackle the challenges that came about. A few decades ago, small-molecule drugs were the main class of therapeutics. Over time, the new generations of therapeutics have provided new functions and brought about additional challenges like stability, intracellular delivery requirements, and viability and expansion. Drug delivery strategies also had to evolve to address these challenges.

“Therapies are more complex and driving innovation for the drug, containment systems, and novel devices that can ideally be administered in an at-home environment,” said Aileen Ruff, vice president and general manager of services and solutions for West Pharmaceutical Services, an Exton, Pa.-based designer and manufacturer of injectable pharmaceutical packaging and delivery systems. “These devices are also becoming smaller, less invasive, and more advanced, which directly impacts manufacturing requirements.”

“One of the leading market forces for us is the overall drug loading and controlled release that can be customized to specific combination medical device requirements, as alternative novel therapies to injectables or ingestible medicines,” said Benny David, director of business development, at NuSil, an Avantor company, which is based in Carpinteria, Calif., and focuses on medical- and space-grade silicone technology. “Women’s health is a growth market for drug delivery device makers, as they improve patient adherence/compliance to pharmaceutical schedules and achieve sustained release of a specific drug from the medical implant.”

Combination products are typically marketed under an authorization type associated with the constituent part that offers the primary mode of action (PMOA) for the combination product. This can mean a new drug application or abbreviated new drug application for a drug PMOA, a biologic license application if it has a biologic PMOA, or either a premarket approval (PMA), de novo certification, or 510(k) if it has a device PMOA.

A single marketing application is usually enough for a combination product, but in some cases the maker might submit separate marketing applications for different constituent parts of the combination product.

“Combination product device manufacturing is subject to a range of evolving regulatory requirements established to protect public health and promote development of safe, effective, and quality of products,” said Ruff. “Overall, combination product device manufacturing requires adherence to a range of regulatory requirements to ensure the safety, efficacy, and quality of the product. Manufacturers must establish robust systems and processes to ensure compliance with these requirements throughout the product lifecycle.”

Thanks to the emergence of patient-centric healthcare, patients’ voices can be heard and recognized as a valuable healthcare resource. It’s been prevalent in the healthcare industry for some time—technological developments support medical and administrative services that can ease and enhance healthcare processes, communications, and workflow.

Patient-centric healthcare emphasizes the patient’s participation, preferences, values, and decisions in diagnosing, treating, and managing their health conditions. In terms of business, a patient-centric approach optimizes resources and lowers operational costs.

“There’s a growing trend toward patient-centric healthcare, which is focused on providing personalized treatment options tailored to individual patient needs,” said Canty. “This is driving development of drug delivery technologies that can be customized to deliver specific dosages and combinations of drugs based on individual patient requirements. The cost of healthcare is also a major concern for patients, healthcare providers, and insurers. Drug delivery technologies that can reduce the need for hospitalization or enable at-home treatment are becoming increasingly popular, as they can help to lower overall healthcare costs. We will start seeing more pharmaceutical companies providing in-home healthcare options for patients.”

Silicones are widely used materials in the medical device industry. The materials have a long history in medical devices and offer versatility and biocompatibility for drug delivery product makers. A silicone system can also be tuned to fit a specific application—manufacturers incorporate silicones in products that require a matrix. When used in this way, the device becomes capable of elution or ion release of the active additive or component.

“Silicone has one of the longest histories of any implantable device polymer, and we draw on our 40+ years of silicone experience to support medical implant and drug delivery applications for our customers and customize chemistry solutions as needed,” said David.

The chemistry behind silicone makes the material versatile and allows it to be custom designed to fit particular drug delivery applications. Its versatile polymer chemistry can offer varying properties that are useful for different applications. The polymer chemistry of silicone leads to a diverse set of material compositions when combined with reactive cross-linkers, catalysts, and reinforcing fillers. Medical-grade silicones must be specifically designed, manufactured, and purified to meet the strictest requirements of the healthcare industry. The silicone products must be manufactured under cGMP standards in facilities indirectly or directly regulated by the FDA or other notified body, and are usually supported with Master Files.

“Silicones possess unique qualities, making them the raw material of choice for various drug delivery devices and systems. As a result of over four decades of successful product development and close customer collaboration, we offer both standard and custom silicone solutions to address the challenges presented in biomaterials applications. Our close cooperation service model delivers support throughout the commercialization process from product design to launch and approval. Our understanding of international regulatory agency (U.S. FDA, EU Notified Bodies, NMPA, MHLW, TGA) requirements and pathways makes us an essential partner to customers submitting marketing authorization applications.” 

“Our excipient-grade silicones can be used in multiple applications, from short-term to long-term medical implant uses, and we’re developing new ways to transform silicone to meet adherence goals of our pharmaceutical, biopharma, and medical device customers,” Benny went on.

Development partners that specialize in drug delivery and combination product manufacturing are using increasingly complex fabrication techniques to tackle the challenge of the increasingly small and complex devices. For example, recent advances in intraocular implants have brought about long-acting, sustained-release devices that are quite tiny and challenging to manufacture.

“Recent advancements in microfabrication and miniaturization techniques are enabling development of smaller, more complex drug delivery devices,” said Canty. “This allows for more precise drug dosing and delivery, as well as greater patient comfort and convenience. Use of automation and robotics in drug delivery device manufacturing is increasing efficiency, reducing costs, and improving quality. 100% quality checks are built into the automation to ensure all critical attributes are inspected before moving onto the next step in the process. This is especially true for high-volume manufacturing processes, where automation can significantly reduce the risk of errors and variability.”

Put to the Test

Developing and submitting a combination product for regulatory approval can be a complicated and in-depth process. Each constituent part of the device must be investigated for safety, as well as for how the constituent parts interact with each other. This requires specialized knowledge about material science, pharmaceutical development, and how those disciplines overlap in the regulatory environment.

“It’s important to partner with a laboratory that is equally qualified and experienced in testing pharmaceutical and biologic products, as well as medical devices—and any combination thereof,” said Christopher Scott, VP of Eurofins Medical Device Testing, a Lancaster, Pa.-based network of laboratories that provides the optimal testing strategy for all types of Class I, II, and III medical devices. “In addition to having expertise in each of those areas, it is vital the laboratory have the infrastructure in place to handle the full spectrum of testing required for combination products.”

That spectrum of testing includes extractable and leachable testing, ISO 10993 chemical characterization, material compatibility, impurity identification, method development, and method validation.

One example is syringe testing, a critical step to develop and commercialize needle-based injection systems for medical use. Testing mechanical properties like break-loose and glide force—described in the ISO 11608 standard—can determine if the device is within standard specifications and reduce likelihood of improper functioning. Other services a testing laboratory might perform on combination products like syringes include transit testing, package and sterile seal integrity testing, sterilization testing, residual EtO (ethylene oxide), EP/USP testing, and siliconization testing.

“A combination product, such as a pre-filled syringe or auto injector, must be shown to maintain effectiveness through the entirety of its shelf-life, as well as follow the rigors of transit from its manufacturing site to its point of use,” said Scott. “Ideally, this should also be a laboratory able to perform full stability testing on the active product, distribution simulations, mechanical functionality, and sterility or Container Closure Integrity (CCIT) testing under the same roof.”

Material characterization is the process of defining chemical properties of a substance or device material. Characterization techniques are used to identify product material, spot the presence of impurities and degradants, or creating a chemical profile for an unknown formulation. Testing partners can provide characterization services for a variety of materials and products—both medical device and pharmaceutical.

Medical device characterization must specifically be performed in accordance with ISO 10993 guidance for the delivery apparatus and other components of interest.

“Additionally, a laboratory must be certified to handle active drug products, which cannot always be assumed when working with a facility focused only on medical devices,” said Scott. “This is particularly important when working with controlled substances or highly potent compounds. There’s no certification specific to combination products, but a laboratory should have all the relevant quality systems and accreditations to meet any testing needs, including cGMP, GLP, ISO 17025, AALAC, ASCA, and ISTA,” said Scott.

To expand upon that string of abbreviations:

• cGMP (Current Good Manufacturing Practice): cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities.
• GLP (Good Laboratory Practice): ensuring quality and integrity of test data related to non-clinical safety studies.
• ISO 17025: enables labs to show they operate competently and generate valid results, promoting confidence in their work both nationally and around the world.
• AALAC (Association for Assessment and Accreditation of Laboratory Animal Care): promotes humane treatment of animals in science through voluntary accreditation and assessment programs.
• ASCA (Accreditation Scheme for Conformity Assessment): an accreditation scheme that capitalizes on the increasingly prominent role that standards play in regulatory science and practice.
• ISTA (International Safe Transit Association): an organization that writes test procedures defining how packages should perform to ensure protection of their contents.

Usability testing and evaluations of device designs also help to drive integral design decisions that may be critical to acquiring regulatory approval and gaining commercial success. Usability testing is evaluating how a medical device is used by patients or other users that will be operating the product prior to going to market. It’s an important part of the development process because it lets medtech developers see if the device has any usability problems or if users have an unsatisfactory experience after or while using the device. The testing gives the developer an opportunity to gather valuable data.

“We perform usability testing throughout the development process of drug delivery/combination products,” said Jessica Young, senior mechanical engineer at Battelle Medical Device Solutions, a Columbus, Ohio-based firm that provides comprehensive medical device development services. “Both formative and summative studies are an integral part of the drug delivery/combination product system (including IFU and Labeling) development process providing evidence for regulatory approval by U.S. FDA and OUS regulatory bodies (IEC 62366).”

Contextual inquiry is a type of ethnographic field study that uses in-depth observation and interviews of a small user sample to gain understanding of work practices and behaviors. Its name describes what makes it such a valuable tool—inquiry in context, which can be for both clinicians and patients operating the device.

“Contextual inquiry is ethnographic research used to investigate user needs, context of use, environmental, cognitive, perceptual, physical, and behavioral factors that influence product usability,” said Young. “Pre-formative and exploratory studies can be performed to elicit user feedback and to collect usability data to help inform device concept development and identify areas of opportunity to improve device design.”

If usability testing isn’t performed early enough in the device’s lifecycle, it can lead to problems for the device including a redesign. A redesign later in the device’s process might lead to a challenging FDA or EU submission process, a delay in timeline, and negatively affect the bottom line.

“User studies help inform usability requirements, minimize use errors, and reduce risk,” said Young. “Increased usability positions a product for successful market entry, decreases risk, causes fewer customer complaints, and reduces development cost by minimizing design rework.”

Usability testing for drug-device combination products is a crucial part of the regulatory approval process, but can also help identify problems and issues with the device. If it isn’t conducted early enough in a device’s design and development, small issues might become big problems. That’s why many manufacturers integrate testing for usability at the beginning of design and development. The earlier an issue is found, the less expensive that issue is to fix, both in terms of cost and time.

“It’s important to enlist a qualified design partner early for usability planning to ensure informed design decisions early in the development process, when adjustments are relatively inexpensive and easy to incorporate into the design process,” said Young. “The later usability processes are introduced into design activities, the lower the impact of usability planning on the cost of design, risk management, and regulatory approval.”

Oval Medical Technologies, an SMC Ltd. company, aims to combine an understanding of patient need with its advanced auto-injector technology so it can customize platforms and create devices that work for any patient or formulation. The company’s technologies are centered around primary drug containers to allow higher viscosities, a wide range of volumes, and fragile molecules to be delivered.

“We have invested in research and development to develop new drug delivery technologies that meet the needs of its OEM partners and the market,” said Canty. “This includes the development of patient-centric auto-injectors. We work closely with OEM partners to understand their specific needs and requirements and develop customized drug delivery solutions that meet their specifications. This includes developing and manufacturing drug delivery devices compatible with specific drugs or therapies and optimizing the design of drug delivery devices for maximum effectiveness.”

Regulatory Concerns and the Future

Regulations for combination products are fairly recent, only available on certain markets, and as a result there aren’t specific regulatory submission formats. Consequently, a combination product is submitted as either a drug or a device and the whole process depends on the PMOA. Research and technological progress has lately been leading to development of novel combination products with no clearly defined PMOA.

The European Union (EU) addresses combination and borderline products by separating the different components, which are governed by different documents. The EU follows a complementary approach—the product isn’t governed in full by one regulation or the other. Determination of the PMOA plays a crucial role by helping to decide which document will be chiefly applied, without excluding other relevant requirements.

The main difference between the U.S. and EU regulatory frameworks is that the FDA treats drug-device combination products as a whole, managed by a specifically dedicated office. In the EU, the different components are separated so distinctive regulations can be applied.

“Arguably most importantly, regulations evolve to improve patient safety,” said Ruff. “The most recent case for this type of change is the EU MDR, which overhauled and tightened many requirements to place devices on the EU market. Changes can also occur through geopolitical reasons, such as U.K. post-Brexit, or Switzerland, both of which now must move away from the EU regulatory framework and create their own. While this new framework could result in a larger regulatory burden for manufacturers, there is also opportunity—both the U.K. and Switzerland are currently evaluating alternate routes to market, such as acceptance of U.S.-approved devices and combination products.”

Combination products are known for their variety, and subsequent diversity, of regulations. Therefore, a “one-size-fits-all” approach to the data requirement isn’t possible.

“Changes can also be brought about from industry feedback,” said Ruff. “Canada issued a consultation in 2021 that solicited opinions on their current combination product framework. Canada plans to incorporate the feedback into their revised regulations.”

To close, a few of the experts weighed in on what to expect in the future for drug-device combination products.

“I anticipate combination medical devices that incorporate multiple drugs to provide different therapies and outcomes, as well as in-situ cured silicones for noninvasive therapies that will include drug delivery applications will be a trend for the future,” said Ruff. 

Article Source: Medical Product Sourcing