Jolyon Paul Mitchell

Jolyon Mitchell Inhaler Consulting Services Inc. · Not applicable

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets prod...

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europ...

We report the outcome of a European Pharmaceutical Aerosol Group study evaluating flow rate-rise times for reduced Next Generation Impactor (rNGI), Fast-Screening Impactor (FSI) and Fast-Screening Andersen impactor (FSA) with surrogate low-, medium- and high-resistance DPIs. Time for the flow rate to reach 90% of target (t90) and flow acceleration...

We recorded inhalation waveforms by pneumotachometer (SpiroQuant-H flow sensor, connected to a data recorder) from adult healthy volunteers with basic training in placebo inhaler use. We measured inhaled volume per inspiration (Vi) and peak inspiratory flow rate (PIFR) to explore natural variability within male (M) and female (F) volunteers. Before...

The ‘Miller’ design of mixing inlet enables a cascade impactor to operate at constant flow rate whilst the inhaler-on-test can be evaluated at varying flow rates. Two studies forming part of a cross-industry assessment of mixing inlet internal losses are reported, the first evaluating continuous medication delivery of salbutamol via a nebulizer, th...

We present the results of a computer model of the transient flow behavior of abbreviated impactors (AIM) during testing of dry-powder inhalers. The principles of the model were established in a cross-industry study of full-resolution Next Generation Impactors (NGI) and Andersen impactors (ACI). Here, we apply the model to abbreviated impactors that...

An overview of the benefits combining the Abbreviated Impactor Measurement (AIM) with Efficient Data Analysis (EDA)concepts in the inhaled product lifecycle.

Implementing the AIM concept by reference to new data (2009) from Pfizer (UK)

The adoption of concepts, such as Quality-by-Design, with the development of orally inhaled drug products (OIPs) and associated devices marks a significant development in understanding inhaler performance. However, independent assessments of the management of inhaled therapy continue to report poor compliance, even after training. This article inve...

Provides experimental data of APSD performance of a pMDI and a DPI with the Alberta idealized adult oropharyngeal model measured by NGI compared with corresponding measurements made with USP/PhEur induction port.

This article presents the AeroEclipse* breath actuated jet nebulizer and explains how it functions.

This article describes a laboratory-based comparison of the 'Alberta' idealized child oropharyngeal model with the USP/PhEur throat (induction port) using a pMDI-delivered salbutamol aerosol as the test inhalation product.

This article describes good laboratory practices when implementing the Abbreviated Impactor Measurement concept for the performance testing of orally inhaled products

The focus of performance evaluation of orally inhaled products (OIPs) for delivering therapeutic medication has until recently, and with few exceptions, been on quality control and the associated evaluations necessary in development before batches of the product can be deemed acceptably safe and efficacious to be released to market. There is now an...

This article explores recent developments in methods that are more clinically relevant than some existing pharmaceutical compendium-based procedures for inhaler performance testing, It explores in detail the purposes of clinically appropriate testing.

This article explains in detail good practices for maintenance and use of multi-stage cascade impactors that are required for the aerodynamic particle size distribution measurement to performance test orally inhaled products.

This article is the first in a series of two articles in which the focus is on recent updates to the normative chapters in the United States Pharmacopeia involved with the Inhalation dosage form.

This article is the second in the series relating to manufacturing control in the NGI, in which the focus shifts to the collection cups and the critical jet exit to collection surface (jet-to-plate) distance.

This article, which is first in a series of two describes a series of scenarios in which the pitfalls of the various techniques used in the measurement of aerodynamic particle size distribution of aerosols from inhalers are presented along with information about the applicability of such instrumentation to the various classes of inhaler.

This is the second in a two-part educational series discussing potential pitfalls in testing OIPs and ways to avoid them. The first article focused on aerodynamic particle size distribution (APSD) determination and this article discusses total emitted mass.

This article provides advice on what to look for when assessing aerodynamic particle size distribution (APSD) data from orally inhaled drug products assessed by a multi-stage cascade impactor.

The article explains why the practice of grouping mass of drug deposited on all 7 or 8 sizing stages of a multi-stage cascade impactor into 3 or 4 groupings following regulatory guidance can result in degraded decision making for quality based on the assessment of orally inhaled product aerodynamic particle size distribution (APSD)

This article explores the importance of considering what is both 'necessary' and 'sufficient' to control cascade impactor cut-point values in terms of nozzle diameter control.

This article is second in a series in which the concept of "sufficient" is explored with respect to cascade impactor quality specifications. The first article was authored by Dr. Daryl Roberts alone.

The article explains why the metric "fine particle dose" is, by itself, insufficient to define the underlying aerosol aerodynamic particle size distribution (APSD) when undertaking oral inhaled product performance testing.

The article describes how the concept of Efficient Data Analysis (EDA) provides all that is needed to define the underlying aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled drug products.

The article present a new way of approaching a move towards more clinically appropriate performance testing of inhaled drug product by adopting measures that are comparatively simple to implement and using equipment that is available commercially. This strategy is a middle course between the relative simplicity but limited capability to mimic clini...

The purpose of the present laboratory-based investigation was to compare the potential for fugitive emissions from a variety of widely encountered compressed air-driven jet nebulizers and one example vibrating mesh nebulizer during simulated adult tidal breathing, using the short acting bronchodilator, salbutamol (sulfate), as the tracer aerosol.

The purpose of the present study was to use Functional Respiratory Imaging (FRI) in order to compare the predicted delivery medication from a pMDI+VHC and two commonly prescribed mid-resistance DPIs to a representative asthmatic adult respiratory tract by means of representative optimal and sub-optimal inhalation profiles.

We compared the dose delivery characteristics using recorded inspiratory flow profiles generated by patients with varying severity of chronic obstructive pulmonary disease (COPD). The participants were recorded when using a medium inspiratory flow resistance dry powder inhaler compared with inhalation of the same active pharmaceutical ingredients (...

This poster describes the generative, patient centred, design process used in the development of a prototype valved holding chamber (VHC) intended primarily for use 'on-the-go' by adults with persistent asthma or newly diagnosed COPD

It has been claimed that an adequate lung dose should be received above a threshold pressure drop of 10 cm H2O with any DPI, based on the negative pressure generated by the patient's inspiratory effort. We report first the validation of a volumetric flow sensor/recorder simulating adult inhalation in accordance with a standard sinus flow rate-time...

An in vitro study was undertaken to assess what changes occurred to the aerosol deposition patterns from a pMDI (fluticasone propionate (FP); 125 μg/actuation) delivered alone or via an AeroChamber* Plus Flow-Vu* VHC/mouthpiece, when the tongue was intentionally omitted from a model anatomic adult oropharynx. A modified fast screening abbreviated A...

Mucus secretion in the lungs is a natural process that protects the airways from inhaled insoluble particle accumulation by capture and removal via the mucociliary escalator. Diseases such as cystic fibrosis (CF) and associated bronchiectasis, as well as chronic obstructive pulmonary disease (COPD), result in mucus layer thickening, associated with...

Particle size measurement of aerosolized particles from orally inhaled and nasal drug products (OINDPs) can be used to assess the likely deposition distribution in the human respiratory tract (HRT). Size is normally expressed in terms of aerodynamic diameter, since this scale directly relates to the mechanics of particle transport from inhaler to d...

The nasal cavity is a target for both locally and systemically acting medications. However, it is difficult to evaluate drug deposition in the nasal passageways, and in particular the olfactory region where there is the potential to bypass the blood-brain barrier, with different nasal devices and administration techniques. Two variants of a section...

Patients infected with COVID-19 and admitted to hospital often require inhaled bronchodilator therapy to manage breathlessness. US hospitals are considering optimal ways to deliver such medication with pMDIs in short supply; the inhaler segregated from the patient allowing for reuse elsewhere without risk of contamination. In response to questions...

Multi-stage cascade impactors (CI) are accepted for the determination of metrics of the drug mass aerodynamic particle size distributions (APSD) of aerosols emitted from orally inhaled products (OIPs). This is particularly important for products where the drug to excipient ratio or particle density may not be the same in each aerodynamic size fract...

We describe a computational model that captures the physics of the unsteady air-flow startup that accompanies the testing of dry-powder inhalers (DPI) with cascade impactors (CIs) specifically when following methods described in the pharmacopeial compendia. This transient has been measured in a multi-organization study for a wide range of condition...

We report a cross-industry study characterizing flow rate-time profiles of equipment used for testing dry-powder inhalers (DPIs). Nine organizations used the same thermal mass flow sensor to record flow rate-time profiles at the inlet of individual participant compendial DPI test systems including either sample collection tubes (SCT), the Andersen...

Background: In May 2019, the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) held a one-day workshop on digital health tools for respiratory therapies, with speakers representing views of patients, pharmaceutical and technology companies, physicians, a...

Background: Determination of aerosol aerodynamic particle size distributions (APSD) from dry-powder inhalers (DPIs), following quality control procedures in the pharmacopeial compendia, requires that the flow through the measurement apparatus, comprising induction port, optional pre-separator, and cascade impactor, starts from zero on actuation of...

Introduction: Pulmonary drug delivery is a complex field of research combining physics which drive aerosol transport and deposition and biology which underpins efficacy and toxicity of inhaled drugs. A myriad of preclinical methods, ranging from in-silico to in-vitro, ex-vivo and in-vivo, can be implemented. Areas covered: The present review covers...

The present scoping study was designed to determine the potential impact of variable inhalation technique on fine particle mass (FPM) emitted from the widely prescribed Diskus* passive DPI (GSK) compared with inhalation of the same active pharmaceutical ingredients (APIs) via a pMDI with antistatic adult AeroChamber Plus* Flow Vu* VHC either tidall...

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse...

Patients can readily access on-line training videos demonstrating correct inhaler use. This proof-of-concept study explored the impact on patient waveforms and potential drug delivery if patients used such instruction without clinician support. Consent was obtained from three DPI naïve adult volunteers, each of whom was asked to inhale from a Disku...

Instructions for a valved holding chamber (VHC) suggest that the patient should inhale slowly and deeply followed by a breath hold for 5-10 seconds. However, if they are not able to complete such an exercise, they should breath tidally for 2-3 cycles. The aim of this study was to develop a methodology by which breathing profiles can be recorded, ev...

Patients of all ages with asthma are widely prescribed pMDIs with VHC (spacer) following current clinical guidelines [1]. However, both the Aerosol Drug Management Improvement Team (ADMIT) of specialist respiratory clinicians [2] and the International Primary Care Respiratory Group (IPCRG) [3], amongst others [4, 5], have reported that mishandling...

The ability of a patient to inhale forcefully for a given period of time is a prerequisite for effective medication delivery from passive dry powder inhalers (DPIs)]. In the case of the large number of DPIs delivering carrier-based formulations, the inspiratory flow provides energy for powder dispersion to detach the micrometer-sized particles cont...

HISTORIC JUSTIFICATION FOR TWO SEPARATE INHALER TESTING STREAMS • QC methods need to be simple in execution, yet robust • QC methods require highest accuracy and precision • Easily transferred from R&D to production or from one site to another • High throughput • Potentially automatable • Clinically appropriate testing seen as beneficial, but only...

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 velo...

A simple two-compartment, first-order flow resistance model of a cascade impactor reveals the reasons for the major trends observed in the companion, cross-industry study of the transient behavior of the inlet flow rate in compendial DPI test systems. This model is physically reasonable because most of the internal volume of compendial impactors is...

We report outcomes from an EPAG-led cross-industry study, characterizing flow rate/elapsed-time profiles of equipment used for testing dry powder inhalers (DPIs). A thermal mass flow sensor was used by nine organizations in a round-robin approach to record inlet flow rate-time profiles of individual participant compendial test systems (TS) includin...

Evaluations of inhaler use have demonstrated that patient mishandling of pMDIs is commonplace. This study investigated the potential impact on medication delivery associated with three errors: (a) delayed inhalation, (b) over-forceful inhalation, and (c) exhalation instead of inhalation at the time of pMDI actuation. The large adult Aerosol Deliver...

Summary A proof-of-concept experimental study has been undertaken to quantify the force of the aerosol plume emitted from the same pMDI product (Flovent-125 HFA-Evohaler), in combination with VHCs having different inhalation valve types. A sensitive force transducer (0 to 2000 mN) attached to a circular disc-shaped target was mounted perpendicula...

A simple two-compartment, first-order flow resistance model of a cascade impactor reveals the reasons for the major trends observed in the companion, cross-industry study of the transient behaviour of the inlet flow rate in compendial DPI test systems. This model is physically reasonable because most of the internal volume of compendial impactors i...

Nasal cavity breakthrough to the airways of the lungs is associated with nasally inhaled droplets whose size is smaller than ca. 10 μm aerodynamic diameter that behave as an aerosol rather than a spray in terms of their transport. The purpose of the present laboratory-based study was to evaluate a nasal product quality control procedure involving a...

Background: Delivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these...

The multistage cascade impactor (CI) is the standard device for determining the mass­weighted aerodynamic particle size distribution (APSD) of aerosols from orally inhaled products (OIPs). However, the various compendial apparatuses are complex in operation. They are also time consuming to use, and require skilled operators to avoid errors. Once th...

RATIONALE: Inhaled corticosteroid medication is the gold standard for the treatment of underlying inflammatory disease associated with asthma in children. Large volume valved holding chambers (VHCs) have capacities greater than can be emptied in a single breath, especially for children and small infants. This laboratory-based study compared the beh...

RESULTS • A breathing simulator was set to mimick an adult tidal breathing pattern • Tidal volume = 600 cc • Rate/min = 10 cycles • Inspiratory : Expiratory ratio = 1:2 • A filter was replaced minute-by-minute at the mouthpiece to capture the Total Mass (TM) until sputter • Albuterol recovered was quantified by UV-spectrophotometry • In a parallel...

The collection of methods in the pharmacopeial compendia form the basis by which all classes of orally inhaled products (OIPs) are evaluated for quality purposes. The regional regulatory agencies rely on these methodologies as a key component in both the registration process and in subsequent assurance of quality in the context of batch release of...

The collection of methods in the pharmacopeial compendia form the basis by which all classes of orally inhaled products (OIPs) are evaluated for quality purposes. The regional regulatory agencies rely on these methodologies as a key component in both the registration process and in subsequent assurance of quality in the context of batch release of...

Valved holding chambers (VHCs) are widely prescribed for use with pressurized metered dose inhalers (pMDIs) for those patients who have poor coordination of inhaler actuation with the onset of inhalation. The Volumatic® VHC is a large volume (ca. 750-mL) device that is still prescribed for use by small children (as well as some adults) in countries...

The Respimat® SMI (Boehringer Ingelheim, Germany) delivers medication in the form of a standing cloud of micrometer-sized droplets following actuation. If the patient closes their lips over the mouthpiece and inhales at the time of actuation, medication is delivered efficiently to the lungs. However, as with pressurized metered dose inhalers (pMDIs...

We review conditions for asserting that used multi-stage cascade impactors (CIs) are performing aerodynamically in the range specified by the manufacturer for new apparatuses. This “aerodynamic similarity” concept is the fundamental basis for assessing the suitability of used CIs because impactors function largely on the basis of known aerodynamic...

The AIM Concept as an augmentation of full resolution cascade impactor (CI) measurements of the aerodynamic properties of aerosols emitted by OIPs has been in existence for about ten years. A previous EPAG-based survey undertaken five years ago indicated significant interest in the approach, particularly for the screening of candidate products in e...

This pilot study explored how insertion of a representative VHC in the pathway between pMDI and mouth might affect transfer of particles from inhaler mouthpiece to the airways of the lungs. The behaviour of a conventional suspension-formulated ICS (Flovent-125*; fluticasone propionate (FP)) with mass median aerodynamic diameter (MMAD) close to 2.4-...

The assessment through a challenge test of severity of reversible broncho-constrictive disease, such as asthma, is an important part of the diagnosis process as well as defining treatment therapy. Methacholine is frequently used as the inhaled challenge substance and is given by inhalation via a nebulizer for a fixed exposure time to the methacholi...

Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating ti...

The U.S. Pharmacopeia (USP) includes several chapters that contain some type of uniformity test, but there is limited consistency between how the uniformity requirements are formulated in these chapters. The General Chapters - Dosage Forms (GC-DF) Expert Ccommittee of the USP has formed a Joint Data Analysis Subcommittee (JDASC) including members f...

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the perfor...

Electrostatic charge associated with pMDI-emitted aerosols, as well as surface charges acquired by VHCs are known to increase retention of the aerosol within the VHC, thereby reducing medication delivery. A further question relates to whether the inherent molecular polarity/ies of the API(s) delivered by pMDIs into VHCs may be a significant contrib...

It is highly desirable to optimize time taken for inhaler development and quality control-related testing in production. At the same time, regulatory agencies are increasingly looking for particle size-related measures that have been obtained under more clinically realistic conditions. The use of a tapered mixing inlet, in which make-up air is adde...

Many orally inhaled products are supplied with a facemask instead of a mouthpiece, enabling aerosolized medication to be transferred from the inhaler to the lungs when the user lacks the capability to use a mouthpiece. Until recently, laboratory evaluation of an orally inhaled product-facemask was frequently undertaken by removing the facemask, tre...

The purpose of this presentation is to review and describe the importance of effective execution of design controls in the development and manufacturing environment associated with Valved Holding Chambers (VHCs). VHCs are widely prescribed for use with pressurized Metered Dose Inhalers (pMDIs). The focus is on device robustness as a critical qualit...

Pre-treatment of non anti-static Valved Holding Chambers (VHCs) by washing with water and detergent and drip drying prior to use is often recommended in treatment instructions. Priming the interior surfaces with a coating of particulate by wasting actuations from the pressurized Metered Dose Inhaler (pMDI) before use, though wasteful of medication,...

Aerodynamic particle size distribution (APSD) is a critical quality attribute that is specific to the orally inhaled product dosage form. APSD is a critical attribute because it relates drug substance mass to the therapeutic action in the lung, the target organ. This article outlines considerations and associated proposals that might be used to dev...

Facemasks are widely used with valved holding chambers (VHCs) that are prescribed for use with pressurized metered dose inhalers for patients who have difficulty coordinating inhalation with inhaler actuation. Adults also require this type of interface, but there is a wide variety of facial profiles that must be accommodated to minimize dead space...

The compendial approach to determine fine particle dose (FPD) for nebulisers during simulated tidal breathing is to determine delivered dose (DD) for tidal breathing, while fine particle fraction (FPF) is established separately using a cooled Next Generation Impactor (NGI) operated at 15 L/min. FPD is then calculated as the product of DD and FPF. A...