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This review presents the most common disease entities in which combinations of NSAIDs and spasmolytic drugs are used to reduce pain. The benefits of fixed-dose combination products (FDCs) are that they improve the response in people with insufficient monotherapy. Using the synergy or additive effect of drugs, it is possible to obtain a significant therapeutic effect and faster action with the use of smaller doses of individual drugs. In addition, one active ingredient may counteract adverse reactions from the other. Another essential aspect of the use of FDCs is the improvement of medical adherence due to the reduction in the pill burden on patients. It is also possible to develop a fixed-dosed combination product de novo to address a new therapeutic claim and be protected by patents so that the manufacturer can obtain exclusive rights to sell a particular FDC or a formulation thereof. The proposed fixed-dose combinations should always be based on valid therapeutic principles and consider the combined safety profile of all active substances included in the medicinal product. This review aims to identify which combinations of NSAIDs and spasmolytics have been developed and tested and which combinations are still under development.

Pain, a severe public health problem, can affect patient quality of life when inadequately controlled. Considering that pain pathophysiological mechanisms are complex, combining active pharmaceutical ingredients (APIs) with multiple and synergistic mechanisms of action represents a potentially more effective therapeutic approach than conventional monotherapy treatments. In turn, topical drug delivery has clear advantages over other routes of administration, such as high levels of efficacy, better safety profile and great patient compliance. In this context, the combination of two or more APIs in a single dosage form - fixed-dose combination product (FDC) - for topical administration may represent a promising therapeutic option in the field of pain management. Considering the above mentioned, the purpose of this manuscript is to address an overview of some general aspects regarding pain management and FDCs, as well as the regulatory environment that has to be taken into consideration during their development. Special emphasis will be given to fixed-dose combinations for topical administration with analgesic and/or anti-inflammatory activity. Market drivers of the topical FDC currently approved are ultimately pointed out, and new opportunities in pain management highlighted.

Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US.

Background and Aims Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product. Method B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS). Results Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates >90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment. Conclusion Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.

Background: From 1999 to 2010, the annual number of US deaths due to opioid overdose increased about 400% as the number of opioids prescribed yearly also increased by approximately 400%. Over this period, hydrocodone combination products drove the opioid epidemic, as they became the most frequently prescribed medication in the United States. Our objective was to determine if the Drug Enforcement Administration's (DEA) 2014 policy change - which made it more difficult to prescribe hydrocodone combination products by moving them from Schedule III to Schedule II - reduced the total amount of opioid prescriptions as intended. Methods: We conducted a longitudinal analysis of the 10 most populous US states, beginning at the time each state began collecting data on opioid prescribing, and concluding at the end of 2016. The exposure was the DEA-mandated October 6, 2014 hydrocodone combination product schedule change. Results: After the DEA's schedule change for hydrocodone combination products, the total number of opioids prescribed each year per 100 people did not substantially change in California, Florida, Michigan, or New York. Although prescription rates dropped for hydrocodone combination products (CA: 43.2, 35.0; MI: 66.8, 55.6; NY: 20.8, 15.1), the reduction was commensurately counteracted by increased rates for tramadol (CA: 0.2, 9.9; MI: 0.1, 17.3; NY: 0.0, 7.6) and oxycodone (CA: 8.7, 9.7; MI: 10.3, 11.9; NY: 18.1, 18.8). Surprisingly, the other 6 states assessed had no viable mechanism in place for assessing state-wide opioid prescription totals, routinely expunged collected data, or only instituted a reporting mechanism toward the end of our study. Conclusion: Total opioid prescriptions were relatively unchanged following the 2014 DEA-mandated schedule change, however, physicians did change their prescribing habits by substituting tramadol for hydrocodone combination products. This substitution of similar medications for hydrocodone suggests alternative approaches are needed to reduce total US opioid prescription rates. Additionally, the current lack of standardized prescription reporting by states makes detailed opioid prescription analysis alarmingly difficult and insufficient to guide policy or monitor the impact of policy changes.

The regulatory environment is one of the key factors in successfully bringing an innovative medical product, like a drug-device combination product, to market. This paper offers insight into the experiences of those involved in obtaining regulatory approval of drug-device combination products in the European Union and the United States.The research consisted of two phases, qualitative data collection (through semi-structured interviews) and analysis, followed by quantitative data collection (through an online survey) and analysis.A conceptual model was developed that depicted the facilitating factors for obtaining regulatory approval of a drug-device combination product, relevant to the European Union and United States systems, respectively.This model provides, for the first time, a comprehensive understanding of these factors, providing a foundation that could be adapted to reflect specific drug-device combination products. This research demonstrated originality of approach in interviewing thought leaders in the life sciences sector as well as conducting a survey that spans two of the largest jurisdictions for drug-device combination products in the world.

Medical devices and medicinal products have many similarities in their nature, scope or specific medical purposes, and despite the differences in their principal means of action, they are often used in combination. Indeed, many medicinal products depend on medical devices for their administration, and it is increasingly common for medical devices to contain medicinal substances to support their action. Therefore, the combination of medicinal products and medical devices provides additional benefits for patients. However, their higher technical complexity requires a strengthening of their authorisation and certification requirements. In this regard, more comprehensive requirements and classification rules are introduced by a new European regulation on medical devices that fully applies from May 26th 2021. On account of their therapeutic significance, this review aims at gaining insight into the borderline between medical devices and medicinal products in this new 2021 regulatory framework. For the first time, any item containing a medical device and a medicinal product will have both parts evaluated. Through exemplification of both marketed and investigational devices incorporating medicinal substances and drug-device combinations, the new European requirements and their implications are thoroughly illustrated herein.

The US Food and Drug Administration recently granted an approved indication for the first fixed-dose combination antihypertensive (amlodipine) and nonsteroidal anti-inflammatory drug (celecoxib) for treatment of comorbid hypertension and osteoarthritis. This review summarizes available data on this combination product, to be marketed as Consensi (Kitov Pharmaceuticals, Ltd, Tel Aviv, Israel), and discusses its potential place in therapy.

Regenerative cell-based implants using periosteum-derived stem cells were developed for the treatment of large 3 cm fresh and 4.5 centimeter biological compromised bone gaps in a tibial sheep model and compared with an acellular ceramic-collagen void filler. It was hypothesized that the latter is insufficient to heal large skeletal defects due to reduced endogenous biological potency. To this purpose a comparison was made between the ceramic dicalciumphosphate scaffold (CopiOs®) as such, the same ceramic coated with clinical grade Bone Morphogenetic Protein 2 and 6 (BMP) only or a BMP coated cell-seeded combination product. These implants were evaluated in 2 sheep models, a fresh 3 cm critical size tibial defect and a 4.5 cm biologically exhausted tibial defect. For the groups in which growth factors were applied, BMP-6 was chosen at a dose of 344 μg for 3 cm and 1.500 μg or 3.800 μg for 4.5 cm defects. An additional group in the 4.5 cm defect was tested using BMP-2 in a dose of 1.500 μg. For all the cell based implants autologous periosteum-derived cells were used which were cultured in monolayer during 6 weeks. For the fresh defect 408 million cells and for the biologically exhausted tibial defect 612 million cells were drop-seeded on the BMP coated scaffolds. Bone healing was studied during 16 weeks postimplantation, using standard radiographs. While fresh defects responded to all treatments, regardless the use of cells, the biologically hampered defects responded in half of the cases and only if the BMP-cell combination product was used, supporting the concept that cell-based therapies may become attractive in treating defects with a compromised biological status.

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.

Human factors engineering is an important part of combination product development, and regulatory bodies expect certain human factors standards to be met for successful pre-market submissions that demonstrate a product is safe and effective in the hands of end users. This chapter identifies US and international human factors standards for combination products and examines best practices used to develop use-related product documentation that forms the framework of a sponsor’s human factors program, for example, use-related risk analyses (URRA). In addition, strategic implementation of human factors methodologies are discussed in terms of how to (1) start the human factors process early, (2) leverage applicable prior work, (3) keep the global market in mind, and (4) collect labeling-focused data. Challenges that sponsors often encounter during human factors validation testing are also explored, which can include accounting for negative transfer, cautiously relying on training or labeling as a mitigation, providing data-driven design decisions, creating quick reference guides, and determining how to confirm delivery of a full dose.

New patient treatment options continue to drive the need for the development of combination products. Sterility assurance innovation is critical to bring these combination products to market. This innovation requires sterility assurance professionals to collaborate across the broad spectrum of the demands of the health-care industry. Not only does a successful sterility assurance professional need to be an expert in their field, but also they need to be aware of the broad challenges and opportunities associated with bringing a combination product to the market. This book provides an overview as well as introduces exciting new opportunities in each industry sector. The sectors addressed include combination products and their design, terminal sterilization, aseptic processing, packaging, health-care practices as well as the worldwide regulatory environment. The topics associated with each sector are introduced with the perspective of facilitating the development of innovative new combination products.

As their name suggests, combination products consist of drug, device, and/or biologic components combined together at the point of administration into a patient. Where the combination product is kit that is assembled by the physician immediately prior to use, the individual components can be sterilized by specific means suitable for that component’s particular properties. Where the product is provided precombined, one or more of the components may be sensitive to particular methods of sterilization and the challenge becomes one of developing a process that can assure sterility without compromising the any of the fundamental properties of those components. This chapter discusses some of those challenges with reference to a number of case studies.

Core to managing a combination product’s life cycle is a quality system outlining robust design controls and risk management processes. Competent monitoring processes and a multidisciplinary governance structure providing oversight empower efficient and patient-centric product development while facilitating accountability and management awareness throughout.

Most of the biological products currently in development or entering the market are some form of combination products for rapid systemic administration. This has prompted the adoption of a patient-centric approach during development, where convenience to patient is a critical differentiation factor. Therefore, the device ability potential of the candidate molecules emerging from discovery research should be de-risked before moving into development. Important aspects to evaluate are the tendency of constructs to have good solution energetic as measured by several surrogate techniques such as virial coefficients in diluted solutions and the binding energy extracted from induced liquid-liquid phase separation. Low positive binding free energy indicates strong attractive inter-protein interactions, low protein solubility, and therefore high probability of self-association. Equilibrium binding thermodynamics allows dissecting the contribution of solution variables and proper linkages for a combination product. It is also shown that lyogels can be created from silk protein, with superior sustain release profile by modulating hydrophobic and hydrophilic interactions between lyogel and the loaded protein.

Biopharmaceuticals are most often administered to patients subcutaneously by way of a device delivery system, with these two components – biopharmaceutical and device – constituting the combination product. Combination products that employ different device components for the same drug or biologic and those that employ the same device component across different drugs and biologics necessitate a strong scientific comparability bridge be established. The science-based decision strategies follow a risk-based approach in the generation of needed bridging data and/or the leveraging of prior experience and knowledge for an established drug or device component. An impact analysis has proven a useful method in determining the “right study tool” is applied in generating sufficient comparability data to demonstrate bridging to the to-be-marketed combination product. The approaches and considerations described in this chapter are applicable to all phases of product life cycle: early-stage development, pivotal clinical studies, product launch, and post-approval change management.

Launching a new or improvement to a combination product can bring the patient satisfaction and confirmation but also the potential for an unexpected surprise as they may not be familiar with the combination product or changes made to the on-market product. In addition to planned changes, normal variation in combination product constituent parts may be perceived as a difference to the user and impact their experience with the product. These types of use experiences come back in the form of customer appreciation, complaints, and/or testimonies, through direct access via company product support channels, social media, as well as health care givers. In this chapter, lessons learned from the launch and sustaining engineering of the Humira Autoinjector will be discussed, including examples of design/process improvements based on an understanding of the key functional attributes of the design and constituent parts required to deliver robust autoinjector performance.

Due to perceived cost and time savings, medical device and combination product manufacturers frequently consider the option to combine human factors testing with clinical studies. There are some scenarios in which human factors and clinical testing of medical products can be combined to save time and resources. While guidance documents published by the Food and Drug Administration (FDA) emphasize that most human factors validation testing can fully evaluate use-related safety via simulated use usability testing, there are some cases in which clinical actual use usability testing is needed to fully evaluate use-related safety. This paper suggests synergies between clinical testing and human factors testing, presents challenges faced by human factors practitioners when the two types of testing are combined, and offers best practice recommendations to maximize the chance of successfully evaluating the human factors endpoints.

Low dose mixing and its optimization process parameters are facing more challenges. Moreover, minor variation in a dose will tend to significantly have a huge impact on the products’ performance including safety and efficacy of the dosage form. Hence, the characterization in every stage of product development of a low dose compound is mandatory. For this purpose, glimepiride and metformin in the ratio of 1:500 was formulated into tablet deciphering a fixed-dose combination product. The tablet was prepared by wet granulation method and optimized by time-dependent random mixing. Confocal Raman microscopy was employed for the present work for evaluation of compatibility studies, in-process and post-compression parameters. Further, the microscopical evaluation was done for the particle scout analysis. The obtained results indicated that the powder blend was compatible and provided uniform mixing in 20 min. Microscopical evaluation has shown that glimepiride still existed in the amorphous state even after compression. Moreover, the glimepiride area in the single-layer was found to be 0.06%. With this, we propose that confocal Raman microscopy plays the promising role in the detectability of the glimepiride. Therefore, in future, the layer by layer analysing can be opted to study the entire spatial arrangement of the API and excipients, which may tend to have a better understanding of dissolution and their related parameters.

Therapeutics known as combination products because they combine drug, device, and/or biologic elements can offer important advantages relative to single‐modality products. However, regulatory policy in this arena has lagged relative to increases in product submissions and complexity of these products. In this article we describe how the US Food and Drug Administration (FDA) applied Lean Management methods to improve and streamline the process by which different FDA centers and offices coordinate review of combination products. Therapeutic products that combine drug, device, and/or biologic elements account for an increasing share of medical products. The global market for these combination products is expected to grow at a compound annual rate of 5.6% from 2012–2017,1 higher than rates projected for medical devices2 or prescription drugs.3 Combination products such as drug‐eluting stents, prefilled infusion pumps and inhalers, transdermal patches, antibody‐drug conjugates, and even some digital health technologies comprise approximately one‐third of all medical products under development.4 Combination product submissions to the FDA including new technologies increased 17% in 2015 vs. the previous 5‐year average. Combination products offer potential advantages relative to single‐modality products, including fewer adverse effects, improved adherence, controlled drug release, and targeted delivery. However, regulatory policies have not kept pace with the growing number and complexity of these products.5

The objective of the present study was to design and develop drug-device combination product in particular flunisolide nasal spray (FNS) using quality by design (QbD) approach. Quality target product profile (QTPP) of FNS was defined and critical quality attributes (CQAs), i.e. viscosity (cp) (Y1) and D50 droplet size distribution (DSD) (μm) (Y2) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tools. Plackett-Burman and Box-Behnken designs were used for screening the significant factors and optimizing the variables range, respectively. It was observed that viscosity (cp) (Y1) was significantly impacted by formulation variables X1: propylene glycol (PG) (%) and X2: polyethylene glycol (PEG) 3350 (%), while D50 DSD (μm) (Y2) was significantly impacted by formulation variables X1: PG (%), X2: PEG 3350 (%) and device variable X8: delivery volume (μl). A design space plot within which the CQAs remained unchanged was established at laboratory scale. In conclusion, this study demonstrated how QbD based development approach can be applied to the development of drug-device combination products with enhanced understanding of the impact of formulation, process and device variables on CQAs of drug-device combination products.

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Current regulatory guidelines call for the identification and quantification of chemical compounds which may migrate out of a medical device, combination product, or a drug container closure system, and into an individual. Compounds that migrate from these devices often have little available toxicity data resulting in a major challenge in performing an adequate assessment of biological or toxicological risks and thus potentially compromising patient safety. These limited toxicity data may exist by alternative routes. Therefore, route-to-route extrapolation of the available data may be considered for use in these instances. Here we discuss the factors to consider when performing route-to-route extrapolations for L&E compounds beginning with historic and regulatory approaches. This will be followed by a review of pharmacokinetic and pharmacodynamic considerations regarding the applicability of route-to-route extrapolation. Finally, we will discuss route-specific considerations and the derivation of safe exposure limits.

Prefilled syringes, pen injectors, inhalers, auto-injectors, and transdermal patches are all examples of products that combine a drug or biologic with a delivery device. These combination products are increasing in popularity and promise to reduce the cost of healthcare delivery while improving patients’ quality of life. As with other medical devices, makers of combination products are required by regulators to validate that their products can be used safely and effectively by intended users in intended use environments. This typically includes conducting human factors validation testing. While conceptually similar, there are differences in the design of human factors validation tests of combination products. These differences stem from the fact that combination products include use-related risks related to the drug itself, as well as to nuanced differences in how the centers of the FDA who lead the review of combination products and medical device submissions view human factors. In this chapter, we review additional considerations for the design of human factors validation tests for combination products relative to tests for other medical devices. We also discuss a related type of human factors test, that may be used in lieu of a human factors validation test of a combination product involving a generic or biosimilar. For companies that wish to establish that their combination products are substitutable or interchangeable, a comparative use human factors test may be needed.

Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) contain a large amount of potent LNG, and therefore it is important to understand the impact of product design parameters on the in vitro and in vivo performance to ensure safety and efficacy, as well as to avoid serious side effects resulting from dose dumping. LNG-IUS is a complex drug-device combination product, and its formulation design, requires consideration of additional factors such as device configuration and dimensions, in addition to formulation and processing parameters. In this study, ten qualitatively (Q1) and quantitatively (Q2) equivalent LNG-IUSs were manufactured with differences in source (supplier) and dimensions (i.e., thickness) of the outer membrane, drug particle size, dimensions of the drug reservoir (i.e., inner diameter), as well as configuration of the entire IUS. A real-time in vitro release testing method was developed for the LNG-IUSs. In addition, an accelerated release testing method was developed using hydro-alcoholic media in order to reduce the time associated with formulation design. Source variations and thickness of their outer membranes had a great impact on the in vitro drug release from the LNG-IUSs. It was demonstrated that the thicker the outer membrane, the slower the drug release rate. The physicochemical properties of the outer membranes obtained from different sources were characterized to understand their impact on the in vitro drug release of the LNG-IUSs. The composition and mechanical strength may play a role in differences in drug release. The LNG-IUS formulation prepared with the larger drug particle size showed a slightly slower daily release rate. The drug release rates from the compositionally equivalent LNG-IUSs linearly correlated to the surface area of the corresponding drug reservoirs. Another factor that affected the drug release rate was the configuration of the entire IUS. It was shown that the placement of the outer membrane was significant, i.e. whether the ends of the drug reservoir were covered or not. It is important to note that real-time release showed zero-order release kinetics over the test period of approximately 900 days. The current study provides a comprehensive understanding of the impact of product design parameters on the in vitro drug release of LNG-IUSs. In addition, the developed real-time and accelerated release testing methods showed good discriminatory ability for compositionally equivalent LNG-IUSs prepared using different product design parameters.

Compared with single-entity treatments, multientity or combination products have the potential to provide enhanced therapeutic utility. Because they involve components that would normally be overseen by different branches of health authorities (eg, different FDA centers), they raise numerous scientific, regulatory, policy, and review management challenges. This article summarizes the current status of the evolving combination product development landscape and potential options to address key challenges facing combination product developers. Continued collaboration and transparency among regulators, combination product developers, and other stakeholders is essential to streamlining the global combination product development and review process to ensure the availability of high-quality new products that are being used in a way that is safe and effective.

VC-01 is a novel cell replacement therapy being developed as a potential long-term diabetes therapy to more effectively control glycemia, reduce hypoglycemia risk and mitigate diabetes-related complications. VC-01 is derived from directed differentiation of human embryonic stem cells to pancreatic progenitor cells, which are loaded into a durable, retrievable delivery device and then implanted subcutaneously. Once implanted and matured, the cells secrete insulin and other islet hormones in response to blood glucose levels. The delivery device is immunoprotective to implanted cells. VC-01 is currently being evaluated in a 24-month open-label, dose-escalating Phase 1/2 study in T1D patients with minimal insulin-producing β-cell function. Cohort 1 has evaluated product at a subtherapeutic dose to assess initial safety and tolerability and establish implantation techniques. To date, 19 subjects have been implanted and evaluated throughout implantation duration until final product explant. Product has been safe and well tolerated; adverse events have been relatively minor and generally related to the surgical procedure. The delivery device has provided protection against the host adaptive immune system with no evidence of allogeneic or autoimmune rejection or sensitization based upon a sensitive panel of immune function tests. No off-target growth of donor cells has been detected. The potential for prolonged cell survival has been demonstrated, as long as 24 months, but has been inconsistent among subjects and primarily limited by a foreign body response to the device component. Positive immunohistochemical staining for pancreatic islet cell markers NKX6-1, insulin, and glucagon has been observed. These preliminary results demonstrate the immune-protective nature of the encapsulation device and safety of this human stem cell-derived product, but also indicate the ongoing requirement for optimization of the host response to device materials. Disclosure R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. J. Wilensky: None. A. Shapiro: Consultant; Self; Viacyte, Inc., Protokinetix. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc. B. Roep: Consultant; Self; Viacyte, Inc.. Research Support; Self; Viacyte, Inc. R. Wang: Employee; Self; Viacyte, Inc.. Stock/Shareholder; Self; Sanofi. E.J. Kroon: Employee; Self; Viacyte, Inc. M. Scott: Stock/Shareholder; Self; Viacyte, Inc.. K. D'Amour: None. H.L. Foyt: Employee; Self; Viacyte, Inc.. Stock/Shareholder; Self; Viacyte, Inc..

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. 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. 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. 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.

Patients are frequently prescribed a medication that must be administered either by a nasal spray, an inhaler, or a self-injection device. These devices are classified as combination devices by the Food and Drug Administration (FDA) and the Medical Device Regulations (MDR). However, there has been an issue of who and how do these patients get trained. It has long been the stance of the pharmaceutical companies they will not provide training because they provide an Information for Use (IFU) and/or a demo on their website. The issues with either of these means is that neither the FDA, nor the MDR permit them as mitigation for use errors. And, in human factors testing there are considerable numbers of use errors when patients attempt to use the devices.

Objectives This study aimed to design a fixed-dose combination dosage form which provides a sustained release profile for both the freely water-soluble metformin HCl and the poorly soluble gliclazide, two antidiabetic compounds used to treat diabetes mellitus. Methods Hot-melt co-extrusion was used as an innovative manufacturing technique for a pharmaceutical fixed-dose combination product. In this way, a matrix formulation that sustained metformin release could be developed, despite the high drug load in the formulation and the freely soluble nature of the drug. Key findings It was clear that co-extrusion was perfectly suited to produce a fixed-dose combination product with adequate properties for each of the incorporated APIs. A coat layer, containing at least 30% CAPA® 6506 as a hydrophobic polymer, was necessary to adequately sustain the release of the highly dosed freely soluble drug from the 70% metformin HCl-loaded CAPA® 6506 core of the co-extrudate. To obtain a complete gliclazide release over 24-h solubilization in Kollidon® VA, added as a second polymer to the CAPA® 6506 in the coat, was needed. Conclusions Both active pharmaceutical ingredients (APIs), which have different physicochemical characteristics, were formulated in a single dosage form, using co-extrusion.

Objectives To evaluate the effect of ritonavir (RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid (AKBA) and to develop a pharmaceutically acceptable AKBA–RTV combination tablet. Methods A pharmacokinetic (PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. KinetiSol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA–RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. Key findings Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA–RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. Conclusions Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA–RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.

Resistant hypertension (RH) is defined as a condition in which blood pressure remains above 140/90 mm Hg despite the use of at least three antihypertensive drugs, correctly combined and in full doses (including a diuretic). In Poland, the percentage of people suffering from RH is estimated at 10–13% relative to the total number of patients with hypertension. On the other hand, in recent years we have seen a significant increase in the importance of combination products both in Europe and in the United States. Several studies have shown that therapy that includes an average of 3 antihypertensive agents (in the form of combination products) having different mechanisms of action, such as blockers of the renin-angiotensin-aldosterone system (RAAS) in combination with a calcium channel blocker (CCB) or a diuretic, provides blood pressure control in the majority of patients, not only through increased efficacy and tolerability of drugs, but also owing to the simplification of the therapeutic regimen, which promotes the compliance with medical recommendations. In this paper we present the case of a patient with resistant hypertension, whose blood pressure normalised only after the use of a combination product.

A Simple, Precise, Sensitive and time efficient stability indicating reverse phase Ultra Performance Liquid Chromatography (RP-UPLC) method was developed and validated for the simultaneous determination of Acetaminophen and Tramadol impurities present in fixed dose combination product. The components were separated in gradient elution mode using 0.1% Perchloric acid in water and acetonitrile as mobile phase. The column used was Acquity HSS T3 (100 mm x 2.1 mm, 1.8 µ) at a flow rate of 0.5 mL.min−1 with 30°C temperature. Quantification was achieved with detection wavelength of 215 nm. The developed method was validated for specificity, linearity, precision, accuracy, sensitivity (LOD & LOQ) and robustness in accordance with International Conference on Harmonisation (ICH) guidelines. The method is rapid, cost effective for the quantitative determination of Acetaminophen and Tramadol impurities in Acetaminophen and Tramadol tablets dosage forms.