Generic Drug Product Development in Japan: Regulatory Updates During 2014-2019 and the Future.

The growth of healthcare cost is a serious issue in many countries. Generic drug products play an essential role in reducing healthcare costs because they are less costly than the innovator drug products. The regulatory review of generic drug products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). This report introduces the activities of the PMDA from fiscal years 2014-2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, the Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerations to improve their regulation were discussed. More efforts will continue to enable a more efficient and rational generic drug product development and shortening of the review period for partial change approval.

Identifying patients at risk of poor asthma outcomes associated with making inhaler technique errors.

OBJECTIVES: Correct inhaler technique is essential to optimal clinical outcomes in asthma patients. The study aim was to use real-life data from the iHARP database to determine patient factors associated with the performance of inhaler technique errors associated with poor asthma outcomes (as identified in the Critikal study) in patients with asthma prescribed the Turbuhaler (TH), Metered Dose Inhaler (MDI), and Accuhaler (AH) device. METHODS: This was a retrospective cross-sectional study using the iHARP database, a multinational initiative including questionnaires and technique review. Identification of inhaler technique errors specifically associated with poor asthma outcomes was performed by reference to the Critikal study. Multivariable logistic regression was used to identify demographic and clinical factors associated with ≥ 1 of these errors. RESULTS: Factors significantly associated with ≥ 1 inhaler technique error and worsening asthma outcomes for the TH cohort include female gender, very poor to average self-assessment of inhaler technique; for the MDI cohort, female gender, secondary education, and current smoking status; and, in the AH cohort, lack of inhaler technique review by a trained healthcare professional in the previous twelve months and very poor to average self-assessment of inhaler technique. CONCLUSIONS: Numerous specific patient demographic and clinical factors associated with the performance of these errors have been identified, differing according to device. Inhaler technique error associated with poor asthma outcomes is further widespread across devices. Knowledge of these factors and the frequency of their occurence may assist in optimizing device selection and training.

Climate change in healthcare: Exploring the potential role of inhaler prescribing.

Climate change has been described as the biggest global health threat of the 21st century. As a result, governments around the world are committing to legislative change in order to reduce greenhouse gas emissions (GHGEs). The healthcare sector makes a significant contribution to GHGEs and in line with national legislation in the UK, the NHS has recently committed to achieving net zero emissions by 2050. The management of asthma and COPD largely depends on the prescribing of medications that are delivered through inhalers. In the UK, the use of pressurized metered dose inhalers (pMDIs), which rely on hydrofluorocarbon (HFC) propellants accounts for 3.5% of the NHS's total carbon footprint. In contrast, dry powder inhalers (DPIs) have a much lower carbon footprint due to the absence of a HFC propellant. Here we review evidence of the impact of inhaler choices across four domains: environmental impact, clinical effectiveness, cost effectiveness and patient preferences. We find that as well as a lower global-warming potential, DPIs have additional benefits over pMDIs in other domains and should be considered first line where clinically appropriate.

First approval of generic dry powder inhaler drug products in Japan.

The Japanese Ministry of Health, Labour and Welfare (MHLW) published the basic principles of bioequivalence evaluations for generic dry powder inhaler (DPI) drug products in March 2016. The basic principles were formulated to promote the development of effective and safe generic DPI drugs. Based on this document, the Pharmaceuticals and Medical Devices Agency (PMDA) advises generic companies on effective development through consultation meetings. The PMDA generally requires data from in vitro tests, pharmacokinetic studies, and pharmacodynamic or clinical endpoint studies for generic drug development. The MHLW approved the first generic version of the Symbicort Turbuhaler in 30- and 60-dose pack sizes in February 2019. This article presents the concrete data on the first approval of generic DPI drug products based on public information. Graphical abstract.

Development of Dry Powder Inhaler Patient Interfaces for Improved Aerosol Delivery to Children.

The objective of this study was to explore different internal flow passages in the patient interface region of a new air-jet-based dry powder inhaler (DPI) in order to minimize device and extrathoracic aerosol depositional losses using computational fluid dynamics (CFD) simulations. The best-performing flow passages were used for oral and nose-to-lung (N2L) aerosol delivery in pediatric extrathoracic airway geometries consistent with a 5-year-old child. Aerosol delivery conditions were based on a previously developed and tested air-jet DPI device and included a base flow rate of 13.3 LPM (delivered from a small ventilation bag) and an inhaled air volume of 750 mL. Initial CFD models of the system clearly established that deposition on either the back of the throat or nasal cannula bifurcation was strongly correlated with the maximum velocity exiting the flow passage. Of all designs tested, the combination of a 3D rod array and rapid expansion of the flow passage side walls was found to dramatically reduce interface and device deposition and improve lung delivery of the aerosol. For oral aerosol administration, the optimal flow passage compared with a base case reduced device, mouthpiece, and mouth-throat deposition efficiencies by factors of 8-, 3-, and 2-fold, respectively. For N2L aerosol administration, the optimal flow pathway compared with a base case reduced device, nasal cannula, and nose-throat deposition by 16-, 6-, and 1.3-fold, respectively. In conclusion, a new patient interface design including a 3D rod array and rapid expansion dramatically improved transmission efficiency of a dry powder aerosol.

Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler.

The objective of this study was to optimize the performance of a high-efficiency pediatric inhaler, referred to as the pediatric air-jet DPI, using computational fluid dynamics (CFD) simulations with supporting experimental analysis of aerosol formation. The pediatric air-jet DPI forms an internal flow pathway consisting of an inlet jet of high-speed air, capsule chamber containing a powder formulation, and outlet orifice. Instead of simulating full breakup of the powder bed to an aerosol in this complex flow system, which is computationally expensive, flow-field-based dispersion parameters were sought that correlated with experimentally determined aerosolization metrics. For the pediatric air-jet DPI configuration that was considered, mass median aerodynamic diameter (MMAD) directly correlated with input turbulent kinetic energy normalized by actuation pressure and flow kinetic energy. Emitted dose (ED) correlated best with input flow rate multiplied by the ratio of capillary diameters. Based on these dispersion parameters, an automated CFD process was used over multiple iterations of over 100 designs to identify optimal inlet and outlet capillary diameters, which affected system performance in complex and unexpected ways. Experimental verification of the optimized designs indicated an MMAD < 1.6 µm and an ED > 90% of loaded dose. While extrathoracic depositional loss will be determined in future studies, at an operating flow rate of 15 L/min, it is expected that pediatric mouth-throat or even nose-throat aerosol deposition fractions will be below 10% and potentially less than 5% representing a significant improvement in the delivery efficiency of dry powder pharmaceutical aerosols to children.

Inhaled salbutamol from aerolizer and diskus at different inhalation flows, inhalation volume and number of inhalations in both healthy subjects and COPD patients.

The aim of the present study was to demonstrate the effect of inhalation-flow, inhalation-volume and number of inhalations on aerosol-delivery of inhaled-salbutamol from two different dry powder inhalers (DPIs) in both healthy-subjects and chronic obstructive pulmonary disease (COPD) patients. Relative pulmonary-bioavailability and systemic-bioavailability of inhaled-salbutamol, delivered by Diskus and Aerolizer, was determined in 24-COPD patients and 24-healthy subjects. The healthy-subjects and the COPD-patients participated in the study for 7 days in which they received 4 study doses of 200 µg salbutamol (one slow-inhalation, two slow-inhalations, one fast-inhalation, and two fast-inhalations) in four alternative days with 24 hr washout period after each dose. Two urine-samples were collected from each study subjects. The first was provided 30 min post inhalation (USAL0.5), as an index of relative pulmonary-bioavailability, and the second was pooled to 24 hr post inhalation (USAL24), as an index of systemic-bioavailability. Fast-inhalation resulted in significantly higher USAL0.5 and USAL24 than slow-inhalation (p˂0.05) after one-inhalation in both healthy-subjects and COPD-patients but there was no significant difference between slow and fast-inhalation after two-inhalations. One-inhalation resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at both slow and fast-inhalation (p˂0.05) except USAL0.5 with Diskus at slow-inhalation there was no significant difference. Also, two-inhalations resulted in significantly higher USAL0.5 and USAL24 compared to one-inhalation at slow-inhalation only (p˂0.05). No significant difference was found between Aerolizer and Diskus except in USAL0.5 of one slow-inhalation in both health-subjects and COPD-patients (p = 0.048 and 0.047, respectively). Device-formula relation is present at low inhalation-flow since Diskus resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at slow inhalation than Aerolizer. It is essential to inhale-twice and as hard and deep as possible from each dose when using DPI especially with COPD-patients having poor inspiratory efforts such as elderly patients and children.

Current Understanding of the Equivalence Evaluations for In Vitro Tests on Generic Dry Powder Inhaler Drug Products in Japan.

The Japanese Ministry of Health, Labour and Welfare issued the basic principles for bioequivalence evaluations of generic dry powder inhaler (DPI) drug products in 2016. This document presents the recommendations of the methodology for the effective development of generic DPI drug products. Based on this document, the Pharmaceuticals and Medical Devices Agency (PMDA) advises the efficient development in the consultation meeting with generic companies. The PMDA generally requires the data of in vitro tests, pharmacokinetics studies, and clinical endpoint studies for generic development. In vitro tests play a critical role in the development of the generic versions because these tests are used to predict the efficacy and safety of other populations on whom clinical endpoint studies have not been conducted. We are aware that some points need further discussion, such as the recommendations for at least four groups of stages (group 1: the induction port and pre-separator, group 2: greater than 5 µm, group 3: ranging from 3 to 5 µm, group 4: ranging from 0.8 to 3 µm) for in vitro tests of the generic DPI products. This article shows the current understanding and recommendations with respect to in vitro tests, particularly for at least four groups of stages.

[IS IT NECESSARY TO PROHIBIT SIDE-HOLE CLOSURE IN USE OF THE DRY POWDER INHALERS?]

BACKGROUND: In use of Ellipta (EPT), Diskus (DKS) or Turbuhaler (TBH), an instruction not to close side holes is sometimes given, but validity of such instruction has not been proved. METHOD: Using an inhalation simulator we measured peak inhaled flow (PIF), peak inhaled pressure (PIP) and amount of the drug release from these DPIs before and after closure of side holes (SHC). In the case of EPT, incomplete obstruction was also assessed. RESULTS: SHC increased internal resistance by 2.8 times in TBH, 1.0 in DKS, and 1.28 (incomplete obstruction) and 1.86 (complete) in EPT. Inhaled flows at pressure of -15cmH2O were 14L/min in TBH, 47 in DKS and 34 in EPT (incomplete obstruction). SHC suppressed drug release from TBH but statistical significance was not obtained. Drug release was not suppressed by SHC in DKS, while it was almost half during SHC in EPT. The level of PIF decreased by SHC was serious since fine particles generation is not expected. Such severe decreases were not found in DKS and EPT. CONCLUSION: SHC severely inhibited drug release from TBH, but almost no effects on DKS. Such negative effect was limited in usual use of EPT.

Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor.

The multi-stage inertial cascade impactor is used to determine the mass-weighted aerodynamic particle size distribution (APSD) as a critical quality attribute for orally inhaled products (OIPs). These apparatuses progressively size-fractionate the aerosol passing through a series of stages containing one or more nozzles, by increasing particle velocity. Nozzle sizes for a given multi-nozzle stage can be described collectively by effective diameter ([Formula: see text]), related to the cut-point size, providing the link to aerodynamic diameter. Users undertake stage mensuration periodically to assure that each stage [Formula: see text] remains within the manufacturer's tolerance, but there is no guidance on how frequently such checks should be made. We examine the philosophy that particle size-related specifications of the OIP should determine when an impactor is mensurated. Taking an example of a dry powder inhaler-generated aerosol sampled via a Next Generation Impactor with pre-separator, we find that there are only three critical stages that could have a material effect on the measured APSD specified as four groupings of stages following current regulatory practice. Furthermore, [Formula: see text] for the most critical stage having the smallest nozzle sizes could be relaxed by a factor of four or more before risking an inability to measure the mass fraction of API in the group containing the finest particles to a specification within ± 10% of nominal. We therefore conclude that users should consider letting the specification for APSD performance of an OIP in terms of accepted stage groupings drive the impactor quality requirements and frequency that stage mensuration is undertaken.

Preparation and Quality Evaluation of Salvianolic Acids and Tanshinones Dry Powder Inhalation.

Salvianolic acids and tanshinones both exhibit efficacy in treating idiopathic pulmonary fibrosis (IPF), but their formulation limits their clinical use. This study aimed to prepare the salvianolic acids and tanshinones dry powder for inhalation (SPI) to achieve pulmonary delivery for the treatment of IPF. The variable quantities of salvianolic acids and tanshinones composite powder were optimized using the central composite design-response surface method. Different carriers with various drug-carrier ratios were optimized to prepare SPI. The final optimized formulation of SPI was as follows: InhaLac 230® was selected as the carrier with drug:carrier = 1:6, and the milled lactose InhaLac 400® was added at 5%. The developed SPI characterized with an angle of repose 52.46 ± 1.04°, Carr's index of 34.00 ± 0.50% and showed high lung deposition in vitro, indicating the potential of pulmonary delivery for the treatment of IPF.

Dose uniformity of budesonide Easyhaler® under simulated real-life conditions and with low inspiration flow rates.

Budesonide Easyhaler® multidose dry powder inhaler is approved for the treatment of asthma. Objectives were to determine the delivered dose (DD) uniformity of budesonide Easyhaler® in simulated real-world conditions and with different inspiration flow rates (IFRs). Three dose delivery studies were performed using 100, 200, and 400 µg/dose strengths of budesonide. Dose uniformity was assessed during in-use periods of 4-6 months after exposure to high temperature (30°C) and humidity (60% relative humidity) and after dropping and vibration testing. The influence of various IFRs (31, 43, and 54 L/min) on the DD was also investigated. Acceptable dose uniformity was declared when mean DD were within 80-120% of expected dose; all data reported descriptively. DD was constant (range: 93-109% of expected dose) at all in-use periods and after exposure to high temperature and humidity for a duration of up to 6 months. DD post-dropping and -vibration were unaffected (range 98-105% of expected dose). Similarly, DD was constant and within 10% of expected dose across all IFRs. Results indicate that budesonide Easyhaler® delivers consistently accurate doses in various real-life conditions. Budesonide Easyhaler® can be expected to consistently deliver a uniform dose and improve asthma control regardless of high temperature and humidity or varying IFR.

Powder flow analysis: A simple method to indicate the ideal amount of lactose fines in dry powder inhaler formulations.

Many efforts have been made in the past to understand the function of lactose fines which are given as a ternary component to carrier-based dry powder inhaler formulations. It is undisputed that fines can significantly improve the performance of such formulations, but choosing the right amount of fines is a crucial point, because too high concentrations can have negative effects on the dispersion performance. The aim of this study was to indicate the optimal concentration of fines with a simple test method. For this purpose, mixtures with salbutamol sulfate and two different lactose carriers were prepared with a high shear mixer, measured with a FT4 powder rheometer and tested for fine particle delivery with two different inhaler devices. A correlation between the fluidization energy, measured with the aeration test set up, and the fine particle fractions (FPF) could be proven. This also applied for the aeration ratio, as well as the permeability of the powder samples. In addition, drug-free mixtures hardly differed in their rheological properties from mixtures containing the active pharmaceutical ingredient (API), which indicates that the method could be suitable for cost-saving screening trials. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study.

Optimization of a DPI Inhaler: A Computational Approach.

Alternate geometries of a commercial dry powder inhaler (DPI, i.e., Turbuhaler; AstraZeneca, London, UK) are proposed based on the simulation results obtained from a fluid and particle dynamic computational model, previously developed by Milenkovic et al. The alternate DPI geometries are constructed by simple alterations to components of the commercial inhaler device leading to smoother flow patterns in regions where significant particle-wall collisions occur. The modified DPIs are investigated under the same conditions of the original studies of Milenkovic et al. for a wide range of inhalation flow rates (i.e., 30-70 L/min). Based on the computational results in terms of total particle deposition and fine particle fraction, the modified DPIs were improved over the original design of the commercial device.

Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union.

In Japan, the development of generic oral dry powder inhaler (DPI) drug products for marketing approval has recently increased. The Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. However, guidelines for DPI drug products have been published by the US Food and Drug Administration and the European Medicines Agency. Recently, the basic principles of bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare. The document mainly outlines the current understanding regarding the bioequivalence evaluations of generic DPI drug products based on knowledge from PMDA consultation meetings. In this review, we compared the bioequivalence evaluations of DPI drug products among Japan, USA, and the European Union and discuss future development of generic DPI drug products in Japan.

Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids: Effect of drug, dose, and device.

BACKGROUND AND AIMS: Little information is available on real-life occurrence of oral thrush in COPD patients treated with ICS. We investigated oral thrush incidence in COPD patients prescribed FDC ICS/LABA therapies and assessed whether it is modulated by the ICS type, dose, and delivery device. METHODS: We conducted a historical, observational, matched cohort study (one baseline year before and one outcome year after initiation of therapy) using data from the UK Optimum Patient Care Research Database. We assessed oral thrush incidence in patients initiating long-acting bronchodilators or FDC ICS/LABA therapy. We then compared different combination therapies (budesonide/formoterol fumarate dihydrate [BUD/FOR] and fluticasone propionate/salmeterol xinafoate [FP/SAL]) and devices (DPI and pMDI). RESULTS: Patients prescribed FDC ICS/LABA had significantly greater odds of experiencing oral thrush than those prescribed long-acting bronchodilators alone (adjusted OR 2.18 [95% CI 1.84-2.59]). Significantly fewer patients prescribed BUD/FOR DPI developed oral thrush compared with FP/SAL DPI (OR 0.77 [0.63-0.94]) when allowing for differences in prescribed doses between the drugs. A significantly smaller proportion of patients developed oral thrush in the FP/SAL pMDI arm than in the FP/SAL DPI arm (OR 0.67 [0.55-0.82]). Additionally, in the FP/SAL cohort (both DPI and pMDI), increased risk of oral thrush was significantly associated with high ICS daily dose (OR 1.97 [1.22-3.17] vs low daily dose). CONCLUSIONS: ICS use increases oral thrush incidence in COPD and this effect is dose-dependent for FP/SAL therapies. Of the therapies assessed, FP/SAL pMDI and BUD/FOR DPI may be more protective against oral thrush.

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach.

The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent. The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper. Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Prospective, open-label evaluation of a new albuterol multidose dry powder inhaler with integrated dose counter.

BACKGROUND: Albuterol multidose dry powder inhaler (MDPI) with an integrated dose counter allows patients to track the number of remaining doses and to simplify dosing by eliminating the need to coordinate inhalation with actuation associated with metered-dose inhalers. OBJECTIVE: To evaluate the functionality, reliability, and accuracy of the albuterol MDPI integrated dose counter in a real-world clinical setting. METHODS: This open-label, phase III study enrolled patients ages ≥4 years with asthma or chronic obstructive pulmonary disease. Patients who demonstrated adequate MDPI inhaler technique and ≥90% compliance with dosing and diary completion during a run-in period qualified for treatment with albuterol MDPI with a dose counter (2 inhalations/dose; 90 µg/inhalation) twice daily for up to 50 days. Patient-reported counter readings and patient-reported actuations were recorded in daily diaries and were used to assess dose counter accuracy. An ease-of-use and satisfaction questionnaire was given at the final visit. RESULTS: A total of 317 patients were enrolled in the study. The dose-cycle undercount (i.e., actuation occurred, but the counter display did not count down) was 2.05 per 200 actuations. The estimated mean ± standard error absolute value of the total discrepancy size after 200 actuations was 2.07 ± 0.140. Most patients (83%) were somewhat or very satisfied, and >90% were satisfied with ease of holding and/or handling, using and taking, and inhaling a dose from the device. The albuterol MDPI was generally well tolerated. CONCLUSION: The albuterol MDPI dose counter functioned reliably and accurately. Albuterol MDPI was well tolerated, with a high degree of patient satisfaction in a real-world setting. CLINICAL TRIAL NUMBER: NCT01857323.