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Gerresheimer and Midas Pharma have developed a novel cartridge-based autoinjector concept in which the cartridge as primary packaging is under constant pressure. In this article standard cartridge primary packaging material of five different companies were analyzed for their behavior under long-term pressure. Materials of 3 glass manufacturers and 2 manufacturers for cartridge rubber parts were considered. Within the test program septum stability, septum piercing, glide forces (GF), break-loose forces (BLF), glass breaking as well as a regulatory approved and marketed antibody drug product under pressure were subject to analysis. Under pressure the cartridge septum bulge grew within the first 14 days and then relevantly slowed down. An accelerated study in different atmospheric conditions allowed to extrapolate values for 24 months storage, not showing any signs of decay or problematic septum bulge increase. Pierce forces were in normal ranges and septum rupture could not be observed at the end of 42 days of pressurization. GF and BLF were within acceptable ranges and changes due to pressure could not be observed. Lowest glass breaking pressures at 4922 kPa turned out to be at least 3.5 times higher than pressures used in the autoinjector concept. Degradation of the Adalimumab antibody drug product due to pressure or device fluid pathway could not be observed with size exclusion chromatography, electrophoresis or sub-visible particles tested as a release testing in a GMP setting. [ABSTRACT FROM AUTHOR]

Combination products, amalgamating drugs, biologics, and medical devices, have revolutionized the healthcare landscape with their potential for innovative therapies. However, the intersection of diverse components within these products presents a complex regulatory environment, demanding rigorous attention to safety and efficacy. This article delves into the intricate landscape of regulatory considerations, safety, and efficacy assessments pertaining to combination products--a category at the intersection of drugs, devices, and biologics. The regulatory framework, primarily governed by the U.S. Food and Drug Administration (FDA), necessitates a nuanced classification determining the regulatory pathway. Collaboration between diverse regulatory centers, such as the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH), underscores the integrated approach required for these innovative healthcare solutions. Safety considerations unravel the potential risks and adverse events associated with combining diverse components, emphasizing the need for robust risk assessment and mitigation strategies. The evaluation of efficacy involves sophisticated methodologies, clinical trials, and post-market surveillance, with recent advancements incorporating digital technologies. This comprehensive exploration aims to contribute to the evolving understanding and best practices in the regulatory and scientific realms, fostering collaboration and innovation in the development and assessment of combination products. [ABSTRACT FROM AUTHOR]

Combination products, amalgamating drugs, biologics, and medical devices, have revolutionized the healthcare landscape with their potential for innovative therapies. However, the intersection of diverse components within these products presents a complex regulatory environment, demanding rigorous attention to safety and efficacy. This article delves into the intricate landscape of regulatory considerations, safety, and efficacy assessments pertaining to combination products—a category at the intersection of drugs, devices, and biologics. The regulatory framework, primarily governed by the U.S. Food and Drug Administration (FDA), necessitates a nuanced classification determining the regulatory pathway. Collaboration between diverse regulatory centers, such as the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH), underscores the integrated approach required for these innovative healthcare solutions. Safety considerations unravel the potential risks and adverse events associated with combining diverse components, emphasizing the need for robust risk assessment and mitigation strategies. The evaluation of efficacy involves sophisticated methodologies, clinical trials, and post-market surveillance, with recent advancements incorporating digital technologies. This comprehensive exploration aims to contribute to the evolving understanding and best practices in the regulatory and scientific realms, fostering collaboration and innovation in the development and assessment of combination products.

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4–4.5 µm), fine particle fraction (56–71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations. [ABSTRACT FROM AUTHOR]

Marty Coyne,1,2 Amy Rinaldi,1 Katherine Brigham,1 James Hawthorne,1,2 Dimos Katsaros,1,2 Morgan Perich,2 Nicholas Carrara,1 Flore Pericaud,3 Chris Franzese,1,2 Graham Jones4 1Matchstick, Boonton, NJ, USA; 2University of Rhode Island School of Pharmacy, Kingston, RI, USA; 3Technical Research and Development, Novartis Pharmaceuticals, Basel, Switzerland; 4Technical Research and Development, Novartis Pharmaceuticals, East Hanover, NJ, USACorrespondence: Graham Jones, Technical Research and Development, Novartis Pharmaceuticals, East Hanover, NJ, USA, Email graham.jones@novartis.comBackground: Self-injection of biologics is a mainstay of chronic disease treatment, yet the process of self-injection often causes persistent apprehension and anxiety, distinct from needle phobia. While literature alludes to the role that routines and rituals play in self-injection, there is no comprehensive study on the routines and rituals self-injectors employ, nor of the process by which they are discovered and ingrained.Methods: We conducted a mixed-method, observational pilot ethnography study of 27 patients with plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis with and without prior biologic self-injection experience. Patients submitted self-made videos, photos, and projective exercises of an actual biologic self-injection and completed validated instruments to assess burden of treatment. Videos and photos containing routine and ritual elements were thematically categorized based on functional and emotional benefit, and analyzed for differences based on current biologic, dosing frequency, time on current biologic, and burden of treatment measures.Results: During patients’ initial at-home injections, training gaps became apparent, leading to a process of experimentation aimed at reducing pain/anxiety, increasing confidence, and building a consistent injection process. Routines were present in 27/27 (100%) patients and anchored the time, place, and process for injection, and incorporated approved use steps for the injection device. Ritual elements served as emotional coping strategies for patients and were present in 21/27 (77.8%) of patients.Conclusion: Our findings suggest that providing patients device training using adult learning principles, teaching routines and rituals concurrently, and providing at-home opportunities for practice with a device trainer may be useful strategies to reduce anxiety, avoid unnecessary experimentation, and improve adherence to injection therapy. While further studies are needed to generalize our findings, we posit that routine and ritual elements can be incorporated into existing patient-clinician interactions or novel digital interventions through mobile medical applications, smart training devices, and connected injection ecosystems.Keywords: training, drug delivery device, combination product, patient support, routines, rituals, burden of treatment, chronic disease, injection trainer, mixed methods research

[Display omitted] To improve patient adherence, vaginal pessaries – polymeric structures providing mechanical support to treat stress urinary incontinence (SUI) – greatly benefit from 3D-printing through customization of their mechanics, e.g. infill modifications. However, currently only limited polymers provide both flawless printability and controlled drug release. The current study closes this gap by exploring 3D-printing, more specifically fused filament fabrication, of pharmaceutical grade thermoplastic polyurethanes (TPU) of different hardness and hydrophilicity into complex pessary structures. Next to the pessary mechanics, drug incorporation into such a device was addressed for the first time. Mechanically, the soft hydrophobic TPU was the most promising candidate for pessary customization, as pessaries made thereof covered a broad range of the key mechanical parameter, while allowing self-insertion. From the drug release point of view, the hydrophobic TPUs were superior over the hydrophilic one, as the release levels of the model drug acyclovir were closer to the target value. Summarizing, the fabrication of TPU-based pessaries via 3D-printing is an innovative strategy to create a customized pessary combination product that simultaneously provides mechanical support and pharmacological therapy. [ABSTRACT FROM AUTHOR]

Purpose: The developer and sponsor of new cell-device and protein-device combination products in the United States needs to forecast which classification and designation to the regulatory scheme of biological products or devices would be required for the new products by the Food and Drug Administration (FDA). To improve the predictability and acceptability of the designation of new cell-device and protein-device combination products for innovators, developers, and sponsors, and to encourage the development and early access of new combination products, we proposed new visualization models of the designation pathway and group categorization. Methods: We searched the website of the FDA and the Alliance for Regenerative Medicine (ARM) on May 3, 2021 to identify the regulatory scheme of the FDA's capsular decision cases of cell-device and protein-device combination products, and of the tissue-engineered products approved by the FDA. Results: By introducing a new definition of the primary intended use (PIU) of developers and sponsors extracted from the classification factors of primary mode of action (PMOA), as well as drug-device and biologic-device combination products, we developed new visualization models of the designation pathway and the two-dimensional model of group categorization, and proposed a new group categorization of cell-device and protein-device combination products, focusing on the device component function. Discussion: The new visualization models and the group categorization proposed in this study may increase the predictability and acceptability of the classification of newly developed cell-device and protein-device combination products to regulatory schemes in the US for innovators, developers, and sponsors. [ABSTRACT FROM AUTHOR]

Objective: The developer and sponsor of new combination products in US needs to forecast which classification and designation to the regulatory scheme of drug, biological product, or device would be required for the new products by the Food and Drug Administration (FDA). To improve the predictability and acceptability of the designation of new combination products for innovators, developers, and sponsors, and to encourage the development and early access of new combination products, we proposed new visualization models of the designation pathway and group categorization. Method: We searched the website of the FDA on 15 November, 2020 to identify the regulatory scheme of the FDA's 129 capsular decision cases of device–drug and device–biologics combination products and other publicly available cases the FDA designated to the drug/biologic or device regulatory scheme. Results: By introducing a new definition for primary intended use (PIU) by developers and sponsors extracted from the classification factors of primary mode of action (PMOA), we developed new visualization models of the designation pathway and two-dimensional group categorization. And applying these models to the cases the FDA designated, we proposed a new group categorization of combination products while focusing on the device component function. Conclusions: The new visualization models with PIU and PMOA and the new group categorization focusing on the device component function proposed in this study may increase predictability and acceptability of the classification of newly developed combination products into the regulatory scheme of drug, biological product, and device, for innovators, developers, and sponsors. [ABSTRACT FROM AUTHOR]

The coordinated research project “RESPONSE - Partnership for Innovation in Implant Technology”, which is one of ten BMBF-funded research consortia within the program “Twenty20 - Partnership for Innovation”, is active in the field of medical device innovation. The consortium is currently in the process of unfolding its transfer phase. This involves a portfolio of key innovations for novel medical devices, technologies and processes. Also, RESPONSE is aiming at participative technology development, integrating perspectives of patients, developers, as well as systems and innovation researchers. Particular challenges are arising from the current re-prioritization and re-scheduling of project roadmaps in order to manage and alleviate the effects of the corona crisis.

The consortium RESPONSE is a cooperation of partners from science and industry within the BMBFProgram “Twenty20 - Partnership for Innovation”, 2014- 2021. Current efforts are being made towards the transfer of new products, technologies and processes in the field of medical devices. Here, RESPONSE is focusing on novel concepts of implantable medical devices for cardiovascular, ophthalmologic and otolaryngologic application. Platform technology approaches, such as drug delivery systems for responsive functionalized implants or smart implant technologies, are being used to enable new applications.

Background: This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug-device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If 'other differences' between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested., Methods: The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted., Results: After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed., Conclusion: DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug-device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If 'other differences' are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

Background: The US Food and Drug Administration (FDA) put out a call for comments on new draft guidance for industry "Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA." This call for comments elicited 7 submissions from various organizations in the field of health care products. This article reports on a review conducted on these 7 submissions. The purpose of this review was to identify any commonalities across the different submissions and determine if there was consensus on any point or aspect of the draft guidance. Methods: To identify any commonalities, a heat map plotting the lines of the draft guidance that had raised a comment/suggestion was produced. Also, a thematic analysis was conducted on the comments/suggestions. Results: In total the 7 submissions produced 137 suggestions. The heat map revealed that these suggestions did not focus on any single part of the guidance but were spread throughout the guidance. The thematic analysis conducted on the suggestions found a number of distinct trends. These trends were grouped into 10 primary themes, each with a number of subthemes. Conclusions: It was concluded that guidance from the FDA on this matter is warranted and would be appreciated. However, it was also concluded that based on the distinct trends identified in the suggestions, there are issues that the FDA may wish to consider before publishing their final guidance. [ABSTRACT FROM AUTHOR]

The article offers information about the regulatory pathway for drug-device combination products in U.S. It mentions that U.S. Office of Combination Products responsible for implementing regulations for Combination Products (CP) as well as the issuance of Guidances to help both FDA reviewers and industry sponsors expedite the development and approval of CPs.

The consortium RESPONSE is a cooperation between partners from science and industry within the BMBF-Program “Twenty20 - Partnership for Innovation”, 2014-2021. RESPONSE gives its partners opportunities to put medical device innovations into practice more efficiently. In order to accelerate innovation processes, joint efforts are being made along the entire translation chain. RESPONSE is focusing on the development of novel concepts of implantable medical devices for cardiovascular, ophthalmologic and ENT application. Platform technology approaches are being used to extend the range of device applications. See also: www.response.uni-rostock.de

Graphical abstract Abstract Efficient ocular drug delivery that can overcome the challenges of topical application has been largely pursued. Contact lenses (CLs) may act as light-transparent cornea/sclera bandages for prolonged drug release towards the post-lens tear fluid, if their composition and inner architecture are fitted to the features of the drug molecules. In this review, first the foundations and advantages of using CLs as ocular drug depots are revisited. Then, pros and cons of common strategies to prepare drug-loaded CLs are analyzed on the basis of recent examples, and finally the main section focuses on bioinspired strategies that can overcome some limitations of current designs. Most bioinspired strategies resemble a reverse engineering process to create artificial receptors for the drug inside the CL network by mimicking the human natural binding site of the drug. Related bioinspired strategies are being also tested for designing CLs that elute comfort ingredients mimicking the blinking-associated renewal of eye mucins. Other bioinspired approaches exploit the natural eye variables as stimuli to trigger drug release or take benefit of bio-glues to specifically bind active components to the CL surface. Overall, biomimicking approaches are being revealed as valuable tools to fit the amounts loaded and the release profiles to the therapeutic demands of each pathology. Statement of Significance Biomimetic and bioinspired strategies are remarkable tools for the optimization of drug delivery systems. Translation of the knowledge about how drugs interact with the natural pharmacological receptor and about components and dynamics of anterior eye segment may shed light on the design criteria for obtaining efficient drug-eluting CLs. Current strategies for endowing CLs with controlled drug release performance still require optimization regarding amount loaded, drug retained in the CL structure during storage, regulation of drug release once applied onto the eye, and maintenance of CL physical properties. All these limitations may be addressed through a variety of recently growing bioinspired approaches, which are expected to pave the way of medicated CLs towards the clinics. [ABSTRACT FROM AUTHOR]

Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers. Cardiovascular safety was assessed by echocardiography, electrocardiogram, and telemetry. Toxicology parameters included clinical signs, body weight, gross pathology, and histopathology. There were no treatment-related deaths associated with the PHP procedure with GEN2 filtration, and all animals survived to scheduled necropsy. Assessment of the pharmacokinetic/TK plasma concentrations of melphalan demonstrated that the GEN2 filter was able to extract melphalan from blood with high efficiency and reduce melphalan exposure in the systemic circulation. The hemodynamic, immunosuppressive, immunotoxic, cardiotoxic, and histopathologic effects of melphalan were limited. The significant hemodynamic challenge imposed by filtration resulted in a compensatory tachycardia with supranormal left ventricular function, although no wall motion abnormalities were detected and left ventricular function remained normal. Catecholamines decreased and then quickly rebounded during washout. Transient and reversible effects of treatment on cardiac enzymes, catecholamines, and cytokines and reversible hemodynamic effects without cardiac damage indicated that PHP with melphalan was not cardiotoxic or immunotoxic under the conditions tested, due to high efficiency of the filtration system limiting exposure of melphalan to the systemic circulation. [ABSTRACT FROM AUTHOR]

We demonstrated in a value-added study that the combination of calcium phosphate–based bone substitute (MaxiBone® bioceramics) and simvastatin/poly lactic-co-glycolic acid (SIMm) carriers which were fabricated by GMP pharmaceutical company and underwent our patterned double-emulsion technique can promote bone growth. The average size distribution of SIMm, the encapsulation efficacy, and the in vitro release profile of simvastatin in SIMm over 14 days were investigated in this study. Based on the results of Alizarin Red S staining and alkaline phosphatase activity, the released simvastatin of SIMm can effectively induce osteogenesis of bone marrow mesenchymal stem cells (D1 cells). In the non-union fracture model of animal study, the MaxiBone bioceramics group and MaxiBone bioceramics with SIMm group showed a significant increase in the percentages of new bone matrix compared with the control group and SIMm groups at the 8th and 10th weeks. Moreover, the MaxiBone bioceramics with SIMm group showed the strongest effect in new bone formation among these groups. We concluded that the calcium phosphate–based ceramics of MaxiBone combined with SIMm can accelerate osteogenic differentiation and bone growth in vitro and in vivo. Our results provide a proof of concept that SIMm can play as an osteoinductive material and the combination with bone substitutes with osteoconductive property effectively enhance bone growth, and this treatment is value added for clinical application, especially in the healing of large bone defects or non-union. Graphical abstract. The clinical-grade calcium phosphate–based bone substitute combined SIM/PLGA/HAp microspheres were fabricated by GMP pharmaceutical company to promote bone growth in bone defect model of mice. [ABSTRACT FROM AUTHOR]

Medical device innovations may contribute to the reconstruction of biological functions, and thereby improve the quality of patients’ lives, as well as extend their life expectancy. The coordinated research project “RESPONSE - Partnership for Innovation in Implant Technology” (BMBF program Twenty20 - Partnership for Innovation, 2014 - 2021) is focusing on the development of novel concepts for implantable medical devices for cardiovascular, ophthalmologic and otorhinolaryngologic applications. The joint research efforts of academia and industry in the RESPONSE consortium address the challenges in implant design, biofunctionalization, process development and production. Particular attention is paid to the process of translation of medical device innovations, cost analysis, as well as health technology assessment.

By discussing the relevant requirements of the Principles of Premarket Pathways for Combination Products Guidance , this study analyzes FDA's review concerns for premarket pathways and predicate product selection of device-led combination products' five typical situations, in order to provide reference for Chinese manufacturers and investigators in device-led combination products registration.