Pulmonary & Nasal Drug Delivery - ONdrugDelivery - No 114 - Nov 2020 by ONdrugDelivery Magazine

P24

INTRANASAL DELIVERY OF BIOLOGIC THERAPEUTICS & VACCINES

P28

THE UNTOLD STORY OF NEMERA’S INHALATION FRANCHISE

P62

ECONOMIC OPERATORS: NEW REQUIREMENTS UNDER THE EU MDR

PULMONARY & NASAL DELIVERY

NOVEMBER 30TH 2020 • ISSUE NO 114

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Contents

ONdrugDelivery Issue No 114, November 30th, 2020

PULMONARY & NASAL DELIVERY This edition is one in the ONdrugDelivery series of publications from Frederick Furness Publishing. Each issue focuses on a specific topic within the field of drug delivery, and is supported by industry leaders in that field. EDITORIAL CALENDAR Dec 2020 Connecting Drug Delivery Jan 2021 Skin Drug Delivery: Dermal, Transdermal & Microneedles Jan/Feb Prefilled Syringes & Injection Devices Feb Novel Oral Delivery Systems Mar Ophthalmic Drug Delivery Mar/Apr Drug Delivery & Environmental Sustainability Apr Pulmonary & Nasal Drug Delivery May Injectable Drug Delivery Jun Connecting Drug Delivery Jul Novel Oral Delivery Systems Aug Industrialising Drug Delivery Sep Wearable Injectors Sep/Oct Drug Delivery & Environmental Sustainability Oct Prefilled Syringes & Injection Devices Nov Pulmonary & Nasal Drug Delivery Dec Connecting Drug Delivery EDITORIAL: Guy Furness, Proprietor & Publisher E: guy.furness@ondrugdelivery.com CREATIVE DESIGN: Simon Smith, Creative Director (Freelance) E: simon.smith@ondrugdelivery.com SUBSCRIPTIONS: Audrey Furness, Marketing Executive E: subscriptions@ondrugdelivery.com Print + Digital subscription: £99/year + postage. Digital Only subscription: free. ADVERTISING: Guy Furness, Proprietor & Publisher E: guy.furness@ondrugdelivery.com ONdrugDelivery is published by Frederick Furness Publishing Ltd The Candlemakers, West Street, Lewes East Sussex, BN7 2NZ, United Kingdom T: +44 1273 47 28 28 Registered in England: Company No 8348388 ISSN 2049-145X print / ISSN 2049-1468 pdf Copyright © 2020 Frederick Furness Publishing Ltd All rights reserved

The ONdrugDelivery logo is a registered trademark of Frederick Furness Publishing Ltd. The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

06 -09

An Advanced Customisable Comprehensive DPI Capsule Portfolio Offering Frédérique Bordes-Picard, Business Development Manager for Innovative Products; and Julien Lamps, Product Manager Lonza

12 - 16

Evaluating the Mechanical Properties of “Extra Dry” Hard-Shell Capsules Sion Coulman, Senior Lecturer Cardiff University Mahmoud Farag, Scientific Business Development Manager Qualicaps

19 - 23

An Introduction To Smart Breath-Actuated Nebulisers Edgar Hernan Cuevas Brun, Marketing Manager HCmed Innovations

24 - 27

Intranasal Delivery of Biologic Therapeutics and Vaccines David Ward, Formulation and Manufacturing Lead Intertek

28 - 30

The Untold Story of Nemera’s Inhalation Franchise Raphaële Audibert, Global Category Manager, Inhalation & Dermal; and Niyati Sapatnekar, Global Communications Manager Nemera

33 - 36

How Emotional Intelligence is Driving Improvements and Meeting the Challenges in Pulmonary Drug Delivery Howard Burnett, Vice-President, Global Account Management, & Head of Global Pulmonary Category Aptar

38 - 41

Cold Filling Versus Pressure Filling: The Case for Versatile, Fully Integrated CDMOs Steve Haswell, Process Development and Tech Transfer Team Leader Kindeva

42 - 44

Development and Production of the Respimat® Reusable Inhaler Housing Module Josef Schmid, Program Manager; Markus Müller, Development Engineer; and Nina Zielonka, Mould Engineer Gerresheimer

46 - 49

One-Stop Shop for Total Mixing Solutions for Pharmaceutical Manufacturers Bert Dekens, Application Manager Hosokawa Micron

50 - 52

Company Showcase – MG2 Automation Solutions for Inhalation MG2

53 - 57

Semi-Automation in Inhaler Testing – Exploring the Potential and Practicalities João Pereira, Team Leader R&D Analytical Development; and Raquel Borda D’Água, Associated Analytical Chemist R&D Analytical Development Hovione Mark Copley, Chief Executive Officer; and Anna Sipitanou, Business Development Manager Copley Scientific

58 - 61

PulmoCraft™: Engineering Spray Dried Powders for Pulmonary Delivery Richard Johnson, Founder and CEO Upperton Pharma Solutions

62 - 64

Economic Operators Under the EU MDR: The New Requirements Beth Crandall, Managing Director, Global Solutions Delivery Leader Maetrics

WHO WILL LAUNCH YOU? Speed, Quality, Support and Expertise is at the heart of what we do. It is what drives us and sets us apart. The picture above shows AJ activating our soft mist inhaler MRX004. MRX004 is filled with water, the plume lasts 1.5 seconds and travels at 0.8 m/sec. It has a measuring chamber of 16 μL to deliver an aerosol with an FPF in excess of 60% with an MMAD of 3-4 μm. It is a highly efficient way to deliver drugs to the lungs with a high deposition. It is ready for human use. Be in touch to add your molecules to it.

info@merxin.com www.merxin.com

WE MAKE THE WORLD HEALTHIER O N E B R E AT H AT A T I M E

Lonza

AN ADVANCED CUSTOMISABLE COMPREHENSIVE DPI CAPSULE PORTFOLIO OFFERING Here, Frédérique Bordes-Picard, Business Development Manager for Innovative Products, and Julien Lamps, Product Manager, both of Lonza Capsules and Health Ingredients, discuss the factors driving development in the area of capsule-based dry powder inhalers, and how the company’s Capsugel® Zephyr™ portfolio offering is perfectly positioned to meet and exceed industry’s growing and evolving requirements. Drug developers looking to deliver drugs via the inhalation route can generally choose from a variety of different technology platforms. These include: • Pressurised metered dose inhalers (pMDIs), which are designed to use compressed propellants • Dry powder inhalers (DPIs), which are kinetic, mechanical, dry powder counterparts of pMDIs • Nebulisers and soft mist inhalers. Within these segments there is a range of device types, varying from simple and inexpensive to highly sophisticated, more expensive options such as e-devices to improve patient compliance. In practice, drug development is segmenting along these device lines, for example, drug developers

“Central to the value proposition of cDPIs are the economies and efficiencies related to encapsulating any drug. Along with compressed tablets, capsules are among the most manufactured and best understood dosage forms in existence.” 6

are tending to choose pMDI systems primarily for emergency medications like the bronchodilator albuterol.1 When considering DPI technology, there are three further subdivisions based on how the powder is stored and dosed – capsule, reservoir and blister: • Capsule-based DPIs (cDPIs) meter each dose by containing it in an individual hard capsule and then placing in the aerosolisation chamber for delivery • Reservoir devices hold a more substantial quantity of the formulation within the device and generally use a relatively complex mechanisation to meter the dose • Blister-type devices employ a “magazinefed” approach with each dose presented in its individual blister for aerosolisation. A variety of attributes make DPIs appealing for the delivery of inhalable oral solid doses (OSDs), but cDPIs in particular provide a very strong value proposition from factory to patient. These attributes include manufacturing economies from a cost-of-goods (CoGs) and supply chain perspective, as well as the innate patient-friendly ease-of-use, portability and better dose compliance of the delivery method. Central to the value proposition of cDPIs are the economies and efficiencies related to encapsulating any drug. Along with compressed tablets, capsules are among the most manufactured and best understood dosage forms in existence – and DPIs that use

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Frédérique Bordes-Picard Business Development Manager for Innovative Products T: +33 3 89 20 57 09 E: frederique.bordes-picard @lonza.com

Julien Lamps Product Manager T: +33 3 89 20 57 09 E: julien.lamps@lonza.com Lonza – Capsules and Health Ingredients 10, Rue Timken F-68027 Colmar Cedex France www.lonza.com Copyright © 2020 Frederick Furness Publishing Ltd

Lonza

them only expand upon their intrinsic value. The current prevalence of respiratory diseases is driving a renewed interest in cDPIs. Asthma and chronic obstructive pulmonary disease (COPD) are currently the two leading respiratory conditions globally; according to estimates from the WHO, COPD will become the third leading cause of death worldwide by 2030.2 In response, pharmaceutical development pipelines are focusing on creating effective inhalable compounds that are better at treating asthma and COPD than the current market offering. One of the key considerations for this development is the cost of the compound, as WHO data shows that over 90% of COPD deaths are in low- and middleincome countries.3 Preference for cDPIs In Emerging Markets In emerging markets, there remains a clear preference for the capsule approach, due to the fact that cDPIs generally provide a means of making certain therapies more accessible.4 Asthma and COPD have been underserviced for a long time in these regions. There is significant opportunity to improve the lives of patients by leveraging developments in generic COPD medications and the advantages offered by cDPI-based delivery. For most developers and manufacturers, capsules are a familiar delivery form with readily available, well-established processes and manufacturing lines. Compared with blister and reservoir platforms, where more dedicated lines are needed and there is a significant leap required in technical knowledge and capital expenditure, capsules offer a simpler, more cost-effective route into new markets.

“Reliably consistent emitted doses need to be quickly and thoroughly evacuated from both capsule and device, meaning it is important that the capsule contents remain free flowing – from the point of manufacture to the point of inhalation by the patient.” Key advantages of Capsugel® Zephyr™ capsules include: • Consistent powder release • Customised approach to optimise performance of the end product • Compatible with a large selection of device principles and opening systems • Ideal puncturing and cutting performance • Available in gelatin (Coni-Snap® Gelatin or Coni-Snap® Gelatin-PEG) and HPMC (Vcaps® or Vcaps® Plus) capsules. Support and Value-Added Service Lonza leverages its vast experience and know-how in all aspects of cDPI capsule development to offer its customers a comprehensive range of value-added services as part of its Zephyr™ offering. These include R&D services such as water activity testing; device compatibility testing; powder retention with standard lactose blend; and investigation of the impact of storage conditions on performance. Additionally, on-site technical support is offered for first trial fillings through to scale-up and filling process optimisation. Finally, Lonza provides quality assurance and regulatory support with answering questions from agencies and compiling the required statements for dossier filings.

Device Compatibility There are many “off-the-shelf” cDPI devices with different levels of sophistication. Some consist of only three to four pieces, which makes them very cost effective, and many can be customised in resistance, colour and shapes. The way in which a given device opens a capsule can also vary; some devices use one or several needles to pierce the capsule on the side or on the top, while others have blades that slice open the capsule on the side, and some simply separate the body and cap of the capsule. Ultimately, the compatibility between the device and the capsule is a critical factor when choosing the best capsule materials and designs with which to work. The capsule’s structural integrity is of paramount importance. First, the capsule must withstand sudden piercing without shattering. Second, the capsule must be sufficiently robust to take this blow without being crushed – thus preventing distortion or other factors that would inhibit the full dispersion of the capsule’s entire contents. Structural integrity is therefore a key consideration for developers looking to ensure downstream patient centricity and support patient compliance efforts with their products.

A CAPSULE PORTFOLIO OFFERING TAILORED TO INHALATION Capsules presented as a portfolio allow developers and manufacturers to achieve optimal and consistent performance by customising polymer formulations by adjusting key design parameters including: capsule size and design; polymer/gelling agents; moisture content; lubricant levels; and weight tolerances. Lonza’s Capsugel® Zephyr™ portfolio comprises customised capsules, in both gelatin and hypromellose, optimised to provide impeccable performance and compatibility between the capsule/device and capsule/formulation (Figure 1). Copyright © 2020 Frederick Furness Publishing Ltd

Figure 1: The Capsugel® Zephyr™ DPI Capsule Portfolio offers options in gelatin and HPMC.

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Lonza

Capsugel® Zephyr™ capsules comfortably meet these requirements and are compatible with a large variety of DPI device principles and opening systems. Direct feedback from patients suggests that they are comfortable with loading a device with the medication dose, inhaling and then checking the emptied capsule to ensure the full dose has been taken. Tuneable for Optimal Formulation-Capsule Compatibility Reliably consistent emitted doses need to be quickly and thoroughly evacuated from both capsule and device, meaning it is important that the capsule contents remain free flowing – from the point of manufacture to the point of inhalation by the patient. Ensuring the complete and uninterrupted exit of the capsule’s contents is an aspect of cDPIs that requires focused attention in development. Many existing and in-development DPI formulations tend to be hygroscopic in nature, and as such cause changes in flow properties of the powder. Interactions between the formulation and the capsule are therefore critical. The properties of capsule materials and the specific characteristics of its polymers can either enhance or diminish the performance of the formulation’s flow characteristics. The customisable range of materials and design options offered by Capsugel® Zephyr™ means that the portfolio caters for a wide range of dry powder formulations with widely variable properties, including those containing standard and engineered particles. With the rise of combination products, capsules still present the simplest way of formulating, filling and delivering said products.

Capsule Polymers There are several choices in capsule type using different polymers suitable for encapsulating cDPI formulations. The most popular include: • Hard gelatin capsules (HGCs) • Modified HGCs • Hypromellose capsules (HPMCs). The technology and the material science behind capsule and formulation are well understood and capsule manufacturers are offering a number of solutions for cDPI applications. For example, the Capsugel® Zephyr™ DPI portfolio contains four different varieties of capsule, each customisable. They are: • Coni-Snap® Gelatin DPI, the standard gelatin component of the Capsugel® Zephyr™ portfolio • Coni-Snap® Gelatin-PEG DPI, the robust gelatin component of the Capsugel® Zephyr™ portfolio • Capsugel® Vcaps® DPI HPMC, a plantbased solution within the Capsugel® Zephyr™ portfolio • Capsugel® VCaps® Plus DPI HPMC, a plant-based solution within the Capsugel® Zephyr™ portfolio, without gelling agent. Controlling water content is a particular consideration for many due to the trend towards hygroscopic formulations. Often, capsule loss on drying (LOD) has to be adapted to specific formulation filling properties and stability requirements. Water

Figure 2: Zephyr™ offers LOD range customisation. activity measures can be performed in-house to find out the best range. Zephyr™ DPI portfolio offers LOD range customisation (see Figure 2). HGCs have been successfully used in cDPIs for more than 30 years, during which time they have proved their viability across a broad range of cDPI applications. HPMC capsules, on the other hand, demonstrate excellent properties that address the challenges of some of the newest APIs and formulations, especially towards hygroscopic or water-sensitive formulations that need to be filled under dry environmental conditions.

Figure 3: Water vapour adsorption-desorption of gelatin and HPMC capsules at 25˚C. 8

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Lonza

and Alzheimer’s through systemic delivery. There is also notable interest in developing inhalable compounds for nasal/sinus membrane routes of administration for conditions affecting the central nervous system (CNS).5

CONCLUSION

Figure 4: Individual value plot of percentage powder retention in Capsugel® Vcaps® DPI HPMC capsules under different storage conditions.

“Lonza is creating breakthroughs in capsule and encapsulation technologies that are changing the functional role of capsules in medical research, drug formulation and drug delivery.” The two polymers are quite different with respect to both chemical and physical attributes and the choice between the materials is ultimately based on which has the least impact on the formulation. One substantial difference between the two polymers is the amount of moisture in the capsule. Figure 3 shows the results of an internal Lonza study which looked at the differences in water content between two capsule types equilibrated across a range of relative humidities (RHs). Because many dry powder formulations are hygroscopic or water sensitive, it is not surprising that HPMC capsules have taken a foothold in the cDPI market, given their relative lower moisture content compared with HGC capsules. However, this must be balanced with the triboelectric (electrostatic) properties of the formulation and capsule interface. A dry capsule will exhibit a reduction in dry powder release (i.e. a higher powder retention inside the capsule) primarily due to static charges (Figure 4). Although dry conditions may be required during filling, as well as within the capsule, to ensure the stability of the API or the formulation, it is important to find the right balance to ensure stability while not excessively impacting the emitted dose. According to the results of an internal study Copyright © 2020 Frederick Furness Publishing Ltd

by Lonza, water activity measurements of the formulation can help identify the optimal LOD target for the capsule. Regardless of the polymer chosen, best practice recommends that compatibility between the capsule, formulation and device is well established as a first step in a successful DPI formulation drug strategy. It is a necessary step and the earlier that this analysis occurs in development the better.

BROADER APPLICATIONS ON THE HORIZON By combining polymer science, engineering and formulation know-how within its Capsugel® Zephyr™ DPI portfolio, Lonza is creating breakthroughs in capsule and encapsulation technologies that are changing the functional role of capsules in medical research, drug formulation and drug delivery. Capsules are a highly adaptable form, offering a range of customisation options to ensure formulation suitability and flexibility in size, catering for higher dosing requirements. As a result, there is increasing interest in expanding cDPI delivery beyond respiratory indications to inhalable therapeutics for diseases such as Parkinson’s

As well as for their cost efficiency, cDPIs are recognised for their patient friendliness and overall effectiveness in delivering dry, inhalable therapeutics. As such, cDPIs are becoming the clear choice for delivering a growing number of these best-in-class respiratory therapeutics.6 Looking to the future, cDPIs have become an exciting area of development and look to be an ongoing area of interest for researchers pursuing new chemical entities (NCEs) to treat the unmet needs of a variety of patient groups.7 Lonza’s Capsugel® Zephyr™ DPI portfolio represents a highly customisable offering that can be tailored for optimal capsule-formulation and capsule-device compatibility across the spectrum of industry requirements, supported with value-added R&D, QA and regulatory services.

REFERENCES 1. “FDA Approves First Generic of a Commonly Used Albuterol Inhaler to Treat and Prevent Bronchospasm”. Press Release, US FDA, April 2020. 2. “Burden of COPD”. WHO website. 3. Atkins PJ, “Dry Powder Inhalers: An Overview”. Respiratory Care, 2005, Vol 50(10), pp 1304–1312. 4. Ebert A et al, “A Simple Affordable DPI: Meeting the Needs of Emerging Markets”. ONdrugDelivery Magazine, Issue 80 (Nov 2017), pp 10–14. 5. Erdo F et al, “Evaluation of Intranasal Delivery Route of Drug Administration for Brain Targeting”. Brain Res Bull, 2018, Vol 143, pp 155–170. 6. Ventura Fernandes J, Villax P, “Dry Powder Inhalers: Towards Effective, Affordable, Sustainable Respiratory Healthcare”. ONdrugDelivery, Issue 102 (Nov 2019), pp 5–8. 7. Williams G, “The Future of DPIs: Aligning Design with Market Demands”. Drug Development & Delivery, Nov/Dec 2012, pp 26–29.

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ICOcapÂŽ An easy-to-use dry-powder inhaler for pulmonary treatments

Customized color and logo options

Capsule piercing from two sides

Patented one-piece design

Optimized size, easy handling

CE-marked and Type III DMF

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H&T Presspart Qualicaps

EVALUATING THE MECHANICAL PROPERTIES OF “EXTRA DRY” HARD-SHELL CAPSULES Here, Sion Coulman, PhD, Senior Lecturer, Siamac Parker, PhD Student, and Prof James Birchall, PHD, Professor of Pharmaceutical Sciences, of Cardiff University, alongside Susana Ecenarro, Director of Scientific Business Development, and Mahmoud Farag, Scientific Business Development Manager, of Qualicaps Europe, discuss new developments in low moisture content capsule technology for hygroscopic and very moisture-labile APIs. Dry powder inhalers (DPIs) are breathactuated devices used to deliver drugs to the lung for local or systemic therapy. A DPI consists of two principal components, the inhaler device and a reservoir containing the micronised dry powder formulation. Hard-shell capsules are one such type of reservoir. These are inserted into the DPI and then punctured or cut in situ immediately prior to inhalation. One of the core functions of the capsule is to maintain the physical and chemical stability of the powdered formulation during storage. Increasing interest in the pulmonary delivery of biologics and potentially hygroscopic or very moisture-labile APIs has stimulated demand for capsules that are functional at lower moisture contents than current market-established capsules. The moisture content of capsules at ambient relative humidity, which for pharmaceutical manufacturing is typically in the region of 40–60%, is determined by the inherent properties of the capsule material. Traditional gelatin capsules have a standard moisture specification of 13–16% under typical manufacturing conditions. The water within the capsule shell acts as a plasticiser, helping to maintain the flexibility required for capsule handling and functionality. Reducing the moisture content of the capsule therefore causes an accompanying increase 12

“Increasing interest in the pulmonary delivery of biologics and potentially hygroscopic or very moisture-labile APIs has stimulated demand for capsules that are functional at lower moisture contents than current marketestablished capsules.”

Dr Sion Coulman Senior Lecturer T: +44 2920 876418 E: coulmansa@cardiff.ac.uk Cardiff University Redwood Building King Edward VII Avenue Cardiff CF10 3NB United Kingdom www.cardiff.ac.uk

in the brittleness of the material,1 which is associated with increased risk of physical defects, such as fragmentation during handling or clinical use.2

“EXTRA DRY” CAPSULES Hydroxypropylmethylcellulose (HPMC) capsules have lower moisture contents (4.5–6.5% at 35–55% relative humidity). They do not require water to act as a plasticiser, which prevents brittleness and fragmentation when the capsule moisture content is reduced through exposure to low relative humidity.3 In 2019, an HPMC

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Mahmoud Farag Scientific Business Development Manager E: mfarag@qualicaps.es Qualicaps Europe Avenida Monte Valdelatas, 4 28108 Alcobendas Madrid Spain www.qualicaps.com Copyright © 2020 Frederick Furness Publishing Ltd

Qualicaps

“Whilst the development of XD capsules may provide the pharmaceutical industry with new opportunities for the encapsulation of particularly challenging DPI formulations, it will be important to ensure that this does not come at the expense of the mechanical properties of the capsule.” capsule formulation (Quali-V®-I XD) with a reduced standard moisture content specification of 2.0–3.5% was developed with the aim of exploiting this property.4 These “extra dry” (XD) HPMC capsules are intended to provide an appropriate reservoir for hygroscopic and especially moisturelabile DPI formulations. This new HPMC capsule has been accompanied by the development of an XD gelatin capsule (Quali-G™-I XD; moisture content of 9.0–10.5%), which contains an additional plasticiser that aims to maintain the flexibility of the capsule material at lower moisture content. Polyethylene glycol (PEG) has previously been proposed as a plasticiser in capsules, with the addition of 4% w/w PEG 4000, for example, conferring a reduction in the brittleness of gelatin capsules with low moisture content.5 Whilst the development of XD capsules may provide the pharmaceutical industry with new opportunities for the encapsulation of particularly challenging DPI formulations, it will be important to ensure that this does not come at the expense of the mechanical properties of the capsule. DPI capsules are subject to various mechanical stresses during pharmaceutical processing (i.e. capsule filling, handling, packaging and transport) and when a DPI is used, where capsules are typically de-blistered, inserted into the DPI, punctured or cut and then subjected to the forces within the inhaler that enable aerosolisation of the powdered contents. A significant increase in brittleness at the lower moisture contents of XD capsules could result in a loss of capsule integrity at any of these stages and compromise product manufacture or performance in the hands of the end user, e.g. during de-blistering. Copyright © 2020 Frederick Furness Publishing Ltd

Capsule Formulation (saturated salt)

% Moisture Content of Capsule (+/- standard deviation)

Quali-V®-I (CaCl2)

4.36 (+/- 0.12)

Quali-V®-I XD (LiI)

3.24 (+/- 0.21)

Quali-G™-I (CaCl2)

13.62 (+/- 0.39)

Quali-G™-I XD (LiI)

9.31 (+/- 0.91)

Table 1: The mean moisture contents (%w/w) of Quali-V®-I, Quali-V®-I XD, Quali-G™-I and Quali-G™-I XD formulations, as determined by LOD tests (N=3), after storage over saturated salt solutions of either calcium chloride (CaCl2)or lithium iodide (LiI) for at least two weeks.

TESTING DPI CAPSULES The mechanical properties of DPI capsules can be examined using a range of test methods, both published6–9 and unpublished (bespoke in-house methods). These include a puncture performance test,7,8,9 which uses a material testing machine to characterise the mechanical behaviour of capsule materials upon controlled puncture with a DPI pin. This particular test has been used for various capsules, stored at a range of relative humidities and temperatures.8 Whilst the puncture performance test is directly relevant to the clinical use of capsules in a DPI, more traditional compression testing methods, which provide an indication of the behaviour of the capsule under a crushing load, provide valuable information related to the behaviour of capsules in response to the forces they may experience during manufacture, handling, transport and storage. These testing methods can be used to determine the impact of the reduced moisture content of XD capsules on their elastic (reversible) and plastic (permanent) deformation under known compression forces, as well as the potential for complete loss of capsule integrity, i.e. capsule failure (the ultimate compressive strength). DPI Capsule Test Case Study The following describes a compression test that has been developed to evaluate the mechanical strength of different capsules that, together with a published puncture performance test,9 was used to compare XD capsules with their more established higher moisture content counterparts. The capsules under investigation were: • Quali-V®-I • Quali-V®-I XD • Quali-G™-I • Quali-G™-I XD (containing PEG).

Prior to testing, all hard-shell capsules under investigation were conditioned for at least two weeks within glass desiccators containing saturated salt solutions of either lithium iodide (for XD capsules) or calcium chloride (for “standard” capsules stored at the lower boundary of their specification range), producing a relative humidity of 18% and 34%, respectively. The moisture content of each capsule type was then measured using an oven-based loss on drying (LOD) test (Table 1).10 Capsule puncture tests were conducted using a previously published and established methodology.8,9 Briefly, an angular pin from an RS01 DPI (Plastiape, Osnago, Italy) was mounted in a material testing machine and used to puncture the central section of the capsule dome. This event was measured quantitatively, using a force-displacement curve, and qualitatively by visual inspection under a light microscope. A bespoke compression test was developed using a flat platen, with a diameter greater than the contact surface of the capsule, mounted in a Zwick material testing machine (ZwickRoell, Ulm, Germany). Capsules were mounted on the rig in a horizontal orientation and compression occurred at quasi-static speeds to negate the force of inertia and ensure deformation of the structure at a low strain rate. The test was completed with a detected force of 230 N. Whilst the force-displacement puncture profile of capsules is well established (Figure 1A),9 the compression profile for a hard-shell capsule is less well understood.6 Capsule compression occurs in three stages (Figure 1B). Stage I of the force displacement curve is indicative of the initial contact event between the platen and the capsule body, followed by a negligible observed reduction in capsule diameter prior to elastic deformation.

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Figure 1

Qualicaps

(A)

250

Force (N)

Stage II of the curve characterises elastic deformation of the capsule. If the IV II 6 III I 200 compression test were paused at this stage and the load removed, the capsule would 5 revert to its original shape. A small but 150 4 discernible increase in the gradient of the I II between 3 mm III force-displacement curve 3 100 and 4 mm signifies the limit of the elastic 2 phase for the capsule. This is the maximum 50 extent to which a capsule can be compressed 1 without permanent alteration to its size and shape. In this study we refer to this as the 0 0 0 2 3 4 0 0.5 1 1.5 2 2.5 3 3.5 “elastic 1limit”. 250 Displacement (mm) Displacement (mm) Compression of the capsule beyond its C elastic limit results in plastic deformation, B 250 II I III the third stage of capsule compression. (B) 200 IV Plastic deformation results in a permanent 200 structural change to the capsule shell; 150 the shoulders of the cap and the body 150 begin to buckle under the compressive I II III force that is applied. At this point the 100 I II III capsule is considered to be unacceptable 100 for use. capsule Within formulation Stage III, complete capsule Figure 1: An illustrative example of (A) puncture profiles for a Quali-G™-I capsule (red line) and Quali-V®-I (blue line). This 4 step pro 50 by Torrisi et al and consists of (I) capsule contact and compression, (II) puncture, (III) protrusion described of the tapered tipfragmentation into the capsule dome a failure may also occurpin (i.e. shaft into 50 the capsule. The maxima of this puncture profile is the force required for capsule puncture. (B) capsule A compression profile from a capsule of the shell), which is detected by that rema failed (red dotted line) during a compression test. (B) is an example of the compression profile for capsules tested in this study. The stages of compression a substantial vertical displacement in the contact0and0 initial compression (II) elastic deformation and (III) plastic deformation (permanent change to capsule structure), and can be visualised in th force-displacement curve. 0 2 3 5 3.5 mean elastic limit of the1capsule is denoted as the subtle change 4in4the slope of 0 1 2 3 5 the curve between stage II and stage III. 3 3.5 The mean puncture forces recorded Displacement (mm) Displacement (mm) for Quali-V®-I capsules (3.96 +/- 0.57 N) C conditioned over saturated salts of calcium (C) IIII I I IIIIII chloride (to create a relative humidity of 34%) were not significantly different from those recorded for the XD capsules (3.88 +/0.58 N). Compression tests also indicated comparable performance (Figure 2B) of Quali-V®-I and Quali-V®-I XD capsules. A marginal increase in the compression G™-I capsule (red line) and Quali-V®-I capsule formulation (blue line). This 4 step process, as indicated in the figure, force is(29.7N to 32.7N) at the elastic ® Figure 1: (A) Puncture profiles for a Quali-G™-I (red line) and Quali-V -I (blue line) capsule (red line) and (III) Quali-V®-I capsule (blue This 4 dome step process, as indicated in the figure, is mpression, (II) puncture, protrusion of the formulation tapered pin tip intoline). the capsule and (IV) movement of the needle limit of the XD HPMC capsules suggests capsule formulation. (B) Compression from capsule that remained intact sion, (II) puncture, (III)puncture. protrusion the taperedprofile pin tipfrom intoa athe capsule dome andintact (IV) movement of which the needle rce required for capsule (B)of A compression profile capsule that remained (solid line) and minor decrease in capsule flexibility line) andfor one thatA failed dotted line) during compression test. of the compression profile capsules tested(red in this study. The stages ofa compression can be categorised as line) (I) acapsule quired for(solid capsule puncture. (B) compression profile from a capsule that remained intact (solid and which (C) Visualisation of a capsule at each stage of compression. upon reduction of moisture content. tic deformation (permanent change to capsule structure), and can be visualised in the accompanying images (C). The compression profile for capsules tested in this study. The stages of compression can be categorised as (I) capsule Taken together, however, these data suggest he slope of the curve between stage II and stage III. formation (permanent change to capsule structure), and can be visualised in the accompanying images (C). The (B) that the reduced moisture content of the pe of the (A) curve between stage II and stage III. B A Quali-V®-I XD formulation, compared 8 60 with its more established Quali-V®-I counterparts, is unlikely to have a detrimental 6 practical impact on the flexibility of the 40 HPMC capsule formulation. 4 Quali-G™-I and Quali-G™-I XD also 20 performed comparably in terms of both 2 the puncturing event (Figure 2A) and the compression test (Figure 2B). Both tests 0 0 ® ® therefore indicate that the PEG excipient I D D D -I X X X D ™ I -I -I G™ ®-I X ™ ™ i -G in Quali-G™-I XD capsules is able to ® l li-V i G G a a V l iia lial al Qu Qu mitigate the notable decrease in flexibility Qu ua u u Q Q Q and increased brittleness, even at a moisture Figure 2: (A) Force required to puncture the capsule dome (n=20) and (B) the content of less than 10%.5 Most remarkably, compression force required to initiate permanent deformation to the capsule the compression data (Figure 2B) igure 2: (A) shell The force required to punctureconditioned the capsule dome (n=20) and (B) solutions the compression force required to initiate permanent (n=30) of capsules over saturated of calcium chloride ® ® solutions of calcium chloride (Quali-V®-I, Quali-G™-I) eformation (Quali-V to the capsule (n=30) of capsules conditioned saturated suggests that the XD gelatin capsule, stored -I, shell Quali-G™-I) or lithium iodideover (Quali-V -I XD, Quali-G™-I XD). r lithium iodide (Quali-V®-I XD, Quali-G™-I XD). average Values represent the mean andstandard error bars are the standard deviation. Values represent the mean and error barsaverage are the deviation. at 18% relative humidity, may even be more Force (N)

Force (N)

-I

Q ua liV

Compression Force at Elastic Limit (N)

Q ua liV

-I

Puncture Force (N)

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Qualicaps

“However, whilst these studies indicate that a plasticiser is able to maintain the flexibility of a gelatin capsule at reduced moisture contents, it does not transform the mechanical performance of a gelatin capsule to a point where it is comparable to its HPMC counterparts.” flexible than the standard gelatin alternative stored at a relative humidity of 34%. This exemplifies and reinforces the value of PEG as a capsule excipient.5 However, whilst these studies indicate that a plasticiser is able to maintain the flexibility of a gelatin capsule at reduced moisture contents, it does not transform the mechanical performance of a gelatin capsule to a point where it is comparable to its HPMC counterparts. It was notable that two of the 20 Quali-G™-I and one of the 20 Quali-G™-I XD capsules fractured during compression tests, as indicated by a vertical displacement in the force-displacement curve (Figure 1) and visible fragmentation of the capsule shell. No fractures were detected in either HPMC capsule used in this study (Quali-V®-I and Quali-V®-I XD) and both require lower forces for puncture and compression than gelatin capsules (Figure 2), which indicates greater flexibility.

product or its clinical use. Understanding the mechanical properties of innovative XD capsules is therefore key to determining their commercial and clinical potential. In the study covered in this article, an established puncture test9 and a bespoke compression test method were used to characterise XD capsules and compare them with more clinically and commercially established capsules with a higher moisture content. The study indicated that the reduced moisture content of the XD capsules does not have a significant impact on their mechanical performance. This encourages further evaluation of these low moisture content capsules for the aerosolisation of dry powder formulations to be used in DPIs.

Qualicaps, a Mitsubishi Chemical Holding Corporation company, has over 120 years of experience in manufacturing hard capsules and a strong record of pioneering new forms of drug administration. Qualicaps is responsible for several milestones in the history of hard capsule development, introducing features so widely accepted and trusted that they have since become industry standards. The company takes pride in producing each capsule with the aim of offering specific and optimal solutions for drug delivery and overall health and wellbeing challenges. By way of Qualicaps’ rich history, knowledge, capabilities, global presence and kaiteki values, the company is leading the way for the next-generation capsule.

REFERENCES The authors would like to thank Eleanor Matthews and Katie Roberts of Cardiff University for their significant contributions to the data discussed in this article.

CONCLUSION ABOUT THE ORGANISATIONS The development of capsules with reduced moisture contents and moisture transfer properties will assist with the development of capsule-based DPI products for hygroscopic and very moisture-labile APIs. However, a reduction in capsule moisture content is typically associated with increased capsule brittleness and the risk of physical capsule defects or failure during manufacture of the

ranked the joint top School of Pharmacy in the UK on the basis of its publications, research environment and impact and 12th in the world by the Shanghai World Rankings. The department’s research is highly interdisciplinary, spanning the full translational pathway associated with pharmaceutical medicine.

Cardiff University is a member of the Russell Group of research-intensive universities (ranked 5th overall by the Research Excellence Framework 2014) and has been recognised as a leader in translational science (2nd overall in impact by the Research Excellence Framework 2014). The School of Pharmacy and Pharmaceutical Sciences was

1. Kontny MJ, Mulski CA, “Gelatin capsule brittleness as a function of relative humidity at room temperature”. Int J Pharm, 1989, Vol 54(1), pp 79–85. 2. Huynh BK et al, “An Investigation into the Powder Release Behavior from Capsule-Based Dry Powder Inhalers”. Aerosol Sci Tech, 2015, Vol 49(10), pp 902–911. 3. Majee S, Avlani D, “HPMC as capsule shell material: physicochemical, pharmaceutical and biopharmaceutical properties”.

know drug delivery

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Qualicaps

Int J Pharm Pharm Sci, 2017, Vol 9(10), pp 1–6. 4. Encinas JL, Ecenarro S, “Quali-V Extra Dry: A Novel Capsule For Delivering Hygroscopic Pharmaceutical Drugs”.

ONdrugDelivery Magazine, Issue 99 (Aug 2019), pp 16–18. 5. Podczeck F (ed), Jones BE (ed), “Pharmaceutical Capsules - 2nd Ed.”. Pharmaceutical Press, 2004. 6. Liebowitz SM, Vadino WA,

ABOUT THE AUTHORS Sion Coulman completed his PhD in 2005, studying microneedle-mediated intradermal gene delivery to human skin. He is a Senior Lecturer at Cardiff University with an interest in pulmonary and dermal drug delivery and works at the interface of pharmaceutical science and engineering. Dr Coulman has specific expertise in the design and performance of drug delivery devices, both in the laboratory and clinical practice, and also has active research interests in bioprinting technology and tissue engineering. His research is funded by a diverse selection of national and international funding bodies, charities and commercial partners from the pharmaceutical industry. Mahmoud Farag is a Scientific Business Development Manager at Qualicaps Europe, where he plays an important role in supporting pharmaceutical R&D departments with solid oral dosage developments, as well as capsule-based DPIs. He also leads the Qualicaps participation in different research programmes in collaboration with a number of research centres and universities to further study the properties and performance of inhalation capsules. Mr Farag holds an MSc degree from Uppsala University, Sweden.

Ambrosio TJ, “Determinaion of Hard Gelatin Capsule Brittlenss Using a Motorized Compression Test Stand”. Drug Dev Ind Pharm, 1990, Vol 16(6), pp 995–1010. 7. Birchall JC, Jones BA, Morrissey A, “A Comparison of the Puncturing Properties of Gelatin and Hypromellose Capsules for Use in Dry Powder Inhalers”. Drug Dev Ind Pharm, 2008, Vol 34(8), pp 870–876. 8. Chong RHE et al, “Evaluating the sensitivity, reproducibility and flexibility of a method to test hard shell capsules intended for use in dry powder inhalers”. Int J Pharm, 2016, Vol 500(1–2), pp 316–325. 9. Torrisi BM et al, “The development of a sensitive methodology to characterise hard shell capsule puncture by dry powder inhaler pins”. Int J Pharm, 2013, Vol 456(2), pp 545–552. 10. “Loss on drying”. European Pharmacopoeia, 2005, 2.2.32, pp 50–51.

Virtual Symposium: Drug Delivery Devices 10 March 2021 | BST (UTC+1)

• 1-day Event • Virtual Event

This intensive one-day meeting delves into the latest innovations in medical & drug delivery device research and development. From microneedles, connected devices and inhalation technology to the integration of human factors into device development and combination product development, our symposium will bring together world-leading companies and device developers for a day of discussion, knowledge sharing and focussed networking.

Agenda at a Glance Morning Session: Novel & Improved Drug Delivery Devices • Digital Transformation for Connected Devices • Emerging Smart Technogies In Drug Delivery Devices • Smart/Digihaler Development • Emerging Drug Delivery Technologies for Challenging Indications • Strategic Frameworks For Developing Combination Products Panel Discussion | Regulatory Developments In Drug Device Combinations - International Considerations For Device Developers Afternoon Session: Improved Development & Launch of Drug Delivery Technologies • Inhalation Devices & Combination Products • Combination Product Safety & Long-Term Eﬃcacy • Certiﬁcation of the First Devices Under the EU MDR • Novel Engineering & Materials In Device Development

Benefits to Attending Hear from and meet with the leading figures in the drug delivery & medical devices field, offering in-depth presentations and new ideas you can use to advance your research & technical knowledge Interact with fellow attendees and speakers through the networking features of the Event App as well as during the live Q&As, taking place at the end of each presentation Explore how AI & Smart tech is being implemented in device technology. Presentations consider how these new technologies enhance patient-friendly drug delivery, and enabling technologies for difficult therapeutic targets Gain insights into how digital integrated technologies are changing the face of drug delivery in combination therapies, Advanced Therapeutic Medicinal Products and nanodrug delivery. Learn about the latest in drug device manufacturing technologies

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Visit The Website: www.oxfordglobal.co.uk/virtual-symposium-drug-delivery-devices/ Contact Us: e.hawkings@oxfordglobal.co.uk

ONE CUSTOMER, ONE CAPSULE Capsules are the very essence of Qualicaps速 As a company dedicated to capsules we have a unique perspective on how to contribute to health. Qualicaps速 delivers pharmaceutical-grade capsules together with a comprehensive service along the drug product life cycle through our global team of commercial, scientific and technical services. Quali-V速-I capsules for inhaled drug delivery.

Strict Microbiological Control

Better Aerosolization

Reduced Powder Adhesion

Superior Puncturing Properties

Quali-V速-I Extra Dry, when a minimum moisture content level is required

Inner Surface Control

Lower moisture content (2.0 - 3.5%)

Drug Delivery to the Lungs Conference 9 / 10 / 11 December 2020 Online/virtual conference One of the world’s largest pulmonary drug delivery and respiratory health conferences • 900+ attendees expected

• 47 On-Demand Presentations

• Free registration

• Themed Discussion Forum with live video chat

• 50+ virtual exhibitors • 20 Live lectures

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• Networking Lounge

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HCmed Innovations

AN INTRODUCTION TO SMART BREATH-ACTUATED NEBULISERS In this article, Edgar Hernan Cuevas Brun, Marketing Manager at HCmed Innovations, considers the benefits of smart breath-actuated nebulisers and looks at the latest technology contributing to the evolution of nebulisers.

THE ROLE OF NEBULISERS IN INHALATION THERAPY Inhalation therapy has been proven to provide a more direct and effective treatment for diseases that affect the respiratory system. The active action of inhaled medication used to treat illnesses affecting the respiratory tracts is supported by a lower dose requirement that translates into higher effectiveness and lower incidence of systematic adverse effects.1 Among the devices commonly used in inhalation therapy, nebulisers have long occupied an essential spot. The first nebulisers date back to the 1800s.2 Transitioning from larger jet nebulisers requiring the use of loud compressors, to more recent portable and silent mesh nebulisers that aerosolise liquid medication by relying on ultrasonic frequencies that vibrate a mesh membrane, nebulisers, have established themselves as a top instrument to deliver inhaled medication, especially when it comes to population groups that may struggle with the use of dry powder inhalers (DPIs) and metered dose inhalers (MDIs).3 As is well documented, the use of MDIs and DPIs requires either good co-ordination to successfully deliver medication into the lungs, or high inspiratory flow, both of which can cause the mishandling of these devices, leading to lower therapeutic efficacy. Therefore, the two major groups that greatly benefit from the use of nebulisers are children under the age of five and the elderly. Nebulisers can be a good solution for patients with certain Copyright © 2020 Frederick Furness Publishing Ltd

“In order to improve drug delivery, the incorporation of a mechanism or sensor that triggers aerosol generation during inhalation provides several benefits.” conditions that prevent them inhaling their medication properly with other devices. Some medications that are administered in the form of inhaled drugs include corticosteroids, bronchodilators such as muscarinic antagonist and beta agonists, antibiotics and more recent innovative biologic drugs.3

THE BENEFITS OF BREATHACTUATED NEBULISERS Breath actuation is a feature of nebulisers that has attracted plenty of attention in recent years, particularly when it comes to the development of new inhalation devices. In order to improve drug delivery, the incorporation of a mechanism or sensor that triggers aerosol generation during inhalation provides several benefits.4 One example is the amount of drug released into the environment when users exhale becomes minimal. This is highly favourable when delivering costly APIs. Although the number of breath-actuated nebulisers is comparatively small when

Edgar Hernan Cuevas Brun Marketing Manager T: +886 2 2732 6596 Ext 26 E: henry@hcmed-inno.com HCmed Innovations Rm B, 10F No 319, Dunhua S Rd Da-an District Taipei City Taiwan www.hcmed-inno.com

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HCmed Innovations

analysing the entire group of commercially available devices, evidence of the benefits of breath-actuated devices has increased in the last decade. In some cases, findings suggest that, in addition to the benefits of the delivered dose from breath-activated devices, aerodynamic particle size distribution also remains within the respirable range (2-5 µm), a condition that is fundamental for better lung deposition.4,5 Consequently, smaller amounts of APIs are required for the treatment with these nebulisers. A drawback of this technology is that, as the drug is not continuously aerosolised, nebulisation time can be compromised, resulting in extended periods of time to complete treatment.6 Nonetheless, this can be offset by lower volumes required to reach the same nominal dose.

inhalation of antibiotics could also lead to the development of “In the new era of smart nebulisers, antimicrobial resistance. it is possible to record treatment There is also speculation about the possibility of information and generate logs or spreading diseases through the reports so that medical practitioners inhaled aerosol that is exhaled can assess the status of patients and when droplets are not properly deposited in the lungs. Although decide on future steps for a more the evidence supporting this suitable line of treatment.” claim has not been extensively covered in the literature, several institutes and organisations have advised against the use of nebulisers that medical practitioners can assess the when patients have to be treated for highly status of patients and decide on future steps infectious diseases, such as in the case of for a more suitable line of treatment.10 this year’s covid-19 pandemic, to avoid the The development of cloud platforms spreading of the virus.8 also allows the safe storage of private As a solution, the introduction of information, compiling clinical history breath-actuated nebulisers substantially that can be readily stored and displayed. BREATH ACTUATION EFFECTIVELY reduces the emission of these fugitive Furthermore, smart nebulisers can assist in REDUCES FUGITIVE AEROSOL aerosols, decreasing the amount of API enhancing patient adherence by allowing the being wasted in the environment and set-up of alarms, reminders and the display In some instances, the use of nebulisers has providing a safer surrounding for those of educational material. Several research been undermined due to the existence of who share the space with people receiving studies have reported that the features fugitive aerosols. Fugitive aerosols refer to inhalation treatment. of smart inhalers can help to enhance inhaled aerosols that do not deposit in the patient compliance.11 respiratory tract and are exerted during THE DAWN OF SMART NEBULISERS All of the previously described functions exhalation. Aerosol released directly into the are expected to continue evolving thanks to environment during the exhalation period In the past decade, the Internet of Things the advancements in wireless connectivity. of continuous nebulisation is also known as (IoT) has also begun to penetrate the This is also the case with mobile applications a fugitive aerosol. Both of these definitions medical field. Nowadays, the better known that transmit information via Bluetooth have been reported to be hazardous to Medical IoT describes the principal of using connectivity, which is currently the main people around the individuals receiving connectivity to create a new network that platform to connect inhalation devices to treatment, as particles can remain airborne connects medical professionals, patients and medical clouds through mobile devices. for times ranging from a few minutes to a caregivers, aiming to share data in real number of hours.6 time of a patient’s course of treatment.9 ADVANCEMENTS IN Previous studies have demonstrated According to some specialists, its PATIENT COMPLIANCE that medical professionals and caregivers implementation could eventually become who assist patients during their inhalation the new standard for medical practice. The establishment of new treatment options treatment are exposed to inhaling Patient adherence has long been a with innovative biological approaches may unnecessary medication, which can concern in the treatment of diseases, require tightening up the development of potentially produce toxic side effects. including respiratory conditions such as combination products to optimise treatment. Such is the incidence that more than 45% of asthma and chronic obstructive pulmonary New clinical trials have been focusing on the nominal dose could end up as a seconddisease (COPD). In the case of these and mesh technology as the main source for the hand medical aerosol under continuous other diseases, patients are required to development of new drug-device products. nebulisation. 7 Moreover, constant follow doctors’ instructions accurately The selection of mesh nebulisers over jet and to keep their symptoms ultrasonic nebulisers is supported by the fact under control. Before the that the former products are portable, silent introduction of smart and more suitable to deliver different types “Previous studies have demonstrated nebulisers, physicians had of medication than their counterparts.12 Launched nearly three decades ago, that medical professionals and to rely on the subjective information provided by mesh nebulisers have various advantages. caregivers who assist patients patients that may have Therefore, several companies have created during their inhalation treatment are not always been entirely platforms that allow the customisation of their devices for specific drugs as exposed to inhaling unnecessary accurate.9 However, in the new era of smart nebulisers, combination products.13,14 This is medication, which can potentially it is possible to record indispensable as the final goal is to optimise produce toxic side effects.” treatment information and drug delivery by linking a specific device generate logs or reports so with a corresponding drug. Since each 20

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formulation has different characteristics, this drug-device combination system could only achieve optimal results as a pair.15 Aiming to strengthen compliance and support drug-device combination development, the application of Bluetooth connectivity and near field communication (NFC) technology can add the function to link the usage of nebulisers and specific drugs as an activating mechanism so that the combination product can be used safely. By doing so, the main objective of enhancing compliance can be further reinforced.

HCmed Innovations

Figure 2: Inner reservoir view showing horizontal mesh position.

COMBINING THE LATEST INNOVATIONS The development of new devices targets the incorporation of most of the functions described in the previous sections with the purpose of improving patient adherence, while offering an optimised treatment. It is fundamental for innovative devices to deliver solutions to the market needs, improving treatment conditions and efficiency. The AdheResp breath-actuated mesh nebuliser, developed by HCmed

Figure 1: AdheResp breathactuated mesh nebuliser. Copyright ÂŠ 2020 Frederick Furness Publishing Ltd

Innovations, is a new device that combines breath actuation and connectivity features (Figure 1). In this device, the breath actuation is supported by the incorporation of a pressure sensor that enables the detection of pressure variation, which occurs during inhalation. This variation activates the aerosol generating structure, converting liquid medication into mist. One of the main advantages of this mechanism is that fugitive aerosol becomes virtually negligible as the software enclosed in the device is configured to deliver aerosol within an optimal time range. Bluetooth connectivity is another indispensable tool for smart devices that is part of AdheResp. By allowing the transmission of information from the device to a mobile application, a secure network to store data in the cloud is under development to monitor and solidify patient compliance through a user-friendly interface. Moreover, adherence is also enriched by the addition of NFC technology that binds the drug to the device in a combined system that optimises drug delivery. The optimised product is the result of an extensive and comprehensive development process, which originated from research studies from HCmed, and has matured throughout collaborations established with pharmaceutical companies. Another additional characteristic of the AdheResp device is that the mesh membrane has been strategically placed in a

horizontal position to minimise residual volume, thus becoming an ideal platform for the delivery of high therapeutic drugs (Figure 2). The chamber structure of the device also contributes to the airflow and delivery of medication, operating with the patented mesh technology of HCmed that supports nebulisation of a wide range of medications that include most recent biologic formulations. The aerosol particle size distribution parameters can further be controlled

Figure 3: Front LED-light panel displaying power, Bluetooth and battery status icons.

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HCmed Innovations

the well-being and comfort of patients. Moreover, it comes with a Type-C USB port to facility charging (Figure 4).

new solutions is expected to satisfy an increasingly growing market that demands more effective, simple, connected and affordable options for inhalation devices in order to contribute to the evolution of nebulisers. This new era, more than ever, requires the collaboration of pharmaceutical companies, device developers, physicians and patients to address an expanding population that has been seriously affected by respiratory diseases due to pollution, overpopulation and other factors. Smart breath-actuated mesh nebulisers, such as AdheResp, merge features that could drive further development of inhalation therapy, and that could create a completely new treatment experience in the worldwide fight against diseases. As the development of this type of device continues to flourish, the contribution of each player is indispensable to deliver more effective treatment solutions for patients who require their daily inhalation treatment.

CONCLUSION

ABOUT THE COMPANY

The incorporation of a new series of smart advancements is creating distinctive applications and differentiating devices in the respiratory field. The integration of

HCmed Innovations is focused on the development of drug-device combination products for inhalation therapy. It develops and manufactures portable vibrating mesh nebulisers that offer a mature customisation platform. This technology enables efficient and reliable nebulisation of different types of medication, including small molecule synthetics and large molecule biologics, as either solutions, suspensions or even difficult-to-deliver high viscosity drugs. The newest products include the incorporation

Figure 4: USB Type-C port at the back of AdheResp.

according to the nature of each formulation, ensuring optimal lung deposition. To complete a well-rounded device, the usability of AdheResp was closely examined to present a slick and intuitive design that allows patients from all ages to manoeuvre through the functions of the mesh nebuliser (Figure 3). This device can be easily disassembled to be properly cleaned and disinfected, safeguarding

“The incorporation of a new series of smart advancements is creating distinctive applications and differentiating devices in the respiratory field.”

UNPARALLELED TIGHT TOPIC FOCUS, EVERY ISSUE FOR >100 ISSUES www.ondrugdelivery.com/subscribe 22

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of breath actuation and connectivity features to enhance drug delivery and reinforce patience adherence.

REFERENCES 1. Salvi S, Gogtay J, Aggarwal B, “Use of breath-actuated inhalers in patients with asthma and COPD - an advance in inhalational therapy: a systematic review”. Expert Rev Respir Med, 2014, Vol 8(1), pp 89–99. 2. Sorino C et al, “Inhalation therapy devices for the treatment of obstructive lung diseases: the history of inhalers towards the ideal inhaler”. Eur J Intern Med, 2020, Vol 75, pp 15–18. 3. Kesten S et al, “Development of a novel digital breath-activated inhaler: Initial particle size characterization and clinical testing”. Pulm Pharmacol Ther, 2018, Vol 53, pp 27–32. 4. Ari A, Fink JB, “Breath-actuated nebuliser versus small-volume nebuliser: efficacy, safety, and satisfaction”. Respir Care, 2012, Vol 57(8), pp 1351–1353. 5. Sabato K et al, “Randomized controlled trial of a breath-actuated nebuliser in pediatric asthma patients in the emergency department”. Respir Care, 2011, Vol 56(6), pp 761–770. 6. McGrath JA et al, “Investigation of the Quantity of Exhaled Aerosols Released into the Environment during Nebulisation”. Pharmaceutics, 2019, Vol 11(2), p 75.

HCmed Innovations

7. Ari A, Fink JB, Pilbeam SP, “Secondhand aerosol exposure during mechanical ventilation with and without expiratory filters: An in vitro study”. Ind J Resp Care, 2016, Vol 5, pp 677–682. 8. Fink JB et al, “Reducing aerosolrelated risk of transmission in the era of covid-19: An interim guidance endorsed by the International Society of Aerosols in Medicine”. J Aerosol Med Pulm Drug Deliv, 2020, Vol 12. Epub ahead of print. 9. Chen J et al, ”The effect of electronic monitoring combined with weekly feedback and reminders on adherence to inhaled corticosteroids in infants and younger children with asthma: a randomized controlled trial”. Allergy Asthma Clin Immunol, 2020, Vol 16, 68, e-collection 2020. 10. Daniels T et al, “Accurate assessment of adherence: self-report and clinician report vs electronic monitoring of nebulisers”. Chest, 2011, Vol 140(2), pp 425–432.

11. Chan AH et al, “Adherence monitoring and e-health: How clinicians and researchers can use technology to promote inhaler adherence for asthma”. J Allergy Clin Immunol Pract, 2013, Vol 1(5), pp 446–54. 12. Pritchard JN et al,”Mesh nebulisers have become the first choice for new nebulized pharmaceutical drug developments”. Ther Deliv, 2018, Vol 9(2), pp 121–136. 13. Gessler T, “lloprost delivered via the BREELIBTM nebuliser: a review of the clinical evidence for efficacy and safety”. Ther Adv Respir Dis, 2019, Vol 13, DOI: 10.1177/1753466619835497. 14. Kerwin E, Ferguson GT, “An overview of glycopyrrolate/eFlow® CS in COPD”. Expert Rev Respir Med, 2018, Vol 12(6), pp 447–459. 15. Dhand R, “Intelligent nebulisers in the age of the Internet: The I-neb Adaptive Aerosol Delivery (AAD) system”. J Aerosol Med Pulm Drug Deliv, 2010, Vol 23, Suppl 1(Suppl 1):iii-v.

ABOUT THE AUTHOR Edgar Hernan Cuevas Brun, Marketing Manager at HCmed Innovations, is responsible for the marketing analysis and research of new products as well as the branding of HCmed’s commercially available mesh nebulisers. He has more than five years of experience in the drug delivery field, holding a degree in biomedical engineering and an MBA. He is also in charge of co-ordinating HCmed’s participation and publications in major conferences, such as the European Respiratory Society International Congress and the American Thoracic Society Conference.

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Intertek Melbourn

INTRANASAL DELIVERY OF BIOLOGIC THERAPEUTICS AND VACCINES In this article, David Ward, Formulation and Manufacturing Lead at Intertek Melbourn, looks at how the nasal route of drug administration offers the potential to improve the delivery of biologics, even for very complex molecules such as antibodies – and why strategic formulation is required to make this a reality. Typically, biologic therapeutics and many vaccines are large, complex molecules with a high molecular weight (MW). However, because intranasal delivery can target both topical and systemic delivery via the different tissue types in the nasal cavity (Figure 1), nasal administration has the potential to address a wide range of diseases. There is currently an increased focus on addressing both prophylactic and therapeutic potential against SARS-CoV-2 infection – but other successes to date include a nasal spray delivering the 3.5 kDa polypeptide hormone calcitonin, which has been used for many years to treat postmenopausal osteoporosis. Table 1 lists a selection of other marketed intranasal biologics, as well as some which are currently in

Figure 1: A solid representation of the nasal cavity generated from MRI scans. 24

development. Intranasal vaccines also promise multiple benefits, with the successful launch of influenza vaccines – for example, FluMist (MedImmune) – onto the market as far back as 2003. Biologic drugs are complex molecules; structure is just as fundamental to their function as chemical stability. They are susceptible to a wide range of degradation routes, which can impact the safety and efficacy of the drug.

ADVANTAGES Potential Nose to Brain Route The blood-brain barrier (BBB) presents a major obstacle to the delivery of therapeutics into the central nervous system (CNS), as the majority of large MW substances are severely restricted from crossing the BBB under normal conditions.1 Successful intranasal delivery of biologics such as peptides, proteins, monoclonal antibodies, oligonucleotides and gene and cell therapies via the nose-to-brain route presents a potential strategy for bypassing the BBB, enabling new treatments for Alzheimer’s, Parkinson’s and antipsychotic-induced symptoms, amongst others. Efficacy and Fast Onset of Action Most biologics are susceptible to enzymatic degradation in the gastrointestinal tract, so the typical route of administration is

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David Ward Formulation and Manufacturing Lead T: +44 1763 261648 E: david.ward@intertek.com Intertek Melbourn Saxon Way Melbourn Hertfordshire SG8 6DN United Kingdom www.intertek.com/inhalation Copyright © 2020 Frederick Furness Publishing Ltd

Intertek Melbourn

Compound/Product

Molecule

Therapeutic Target

Status

Calcitonin

Peptide

Osteoporosis

Marketed

Desmopressin

Peptide

Diabetes insipidus, Haemophilia A

Marketed

Oxytocin

Peptide

Start or strengthen uterine contractions during labour

Marketed

Nafarelin

Peptide

As part of a fertility programme, endometriosis

Marketed

Cyanocobalamin

Peptide

Deficiency of vitamin B12

Marketed

Live attenuated influenza vaccine

Virus-based vaccine

Influenza

Marketed

Poor Absorption Nasal delivery of biologics is limited by the low membrane permeability of large MW protein or peptide drugs. Currently marketed peptides, as shown in Table 2, have a MW in the region of 1000 Da – 3500 Da, with calcitonin having the highest MW of 3432 Da.2 This low permeability for some drugs means that formulation with absorption enhancers is necessary and, potentially, larger doses of the active are required to reach the appropriate therapeutic dose.

STRATEGIC FORMULATION REQUIREMENTS

Table 1: Examples of marketed nasal biologics. a subcutaneous injection. When drugs are administrated by the intranasal route, they enter through the respiratory region around the inferior turbinate where the respiratory nasal mucosa is highly vascularised and lined with columnar epithelium cell types, which present a large surface area (>150 cm2) for drug absorption2 and are highly permeable.3 Because the intranasal route avoids enzymatic degradation in the gastrointestinal tract and first-pass hepatic elimination, it therefore reduces the impact of common barriers which limit drug absorption and contributes to a fast onset of action. Patient Adherence Good patient adherence is important for treatment efficacy and this is particularly true for intranasal drug products, which must be administered regularly and consistently to ensure continued therapeutic benefit. Patient satisfaction and comfort with administering the drug according to the correct medication regime is therefore important. The intranasal route is both non-invasive and well tolerated, expanding the possibility for patient self-administration,1 although differences in delivery devices and their handling characteristics can be a factor.4

DISADVANTAGES Mucociliary Clearance The nasal anatomy, by design, is quick to clear material from entry to the airways via mucociliary clearance – a natural process where the nasal mucosa drag mucus and deposited material from the front of the nose to the throat, where it is swallowed. This means there is typically a short window for absorption of nasally delivered drugs to occur. The natural nasal cycle can also affect Copyright © 2020 Frederick Furness Publishing Ltd

absorption rates. This is an approximate two-and-a-half-hour cycle where one side of the nose is more congested than the other, with the process alternating between sides.5 If your product dose consists of only one shot into the nose, then absorption could vary depending on which nostril is used. Marketed Drug

Molecular Weight

Desmopressin

1183 Da

Nafarelin acetate

1321 Da

Oxytocin

1007 Da

Calcitonin

3432 Da

Cyanocobalamine

1355 Da

Table 2: Molecular weight of marketed intranasal peptides.

Strategic formulation for intranasal biologic delivery is important. Formulation can be used to increase residency time in the nasal cavity using bioadhesives or viscosity adjusters to slow down the rapid mucociliary clearance and increase the amount of drug retained in the nasal cavity to allow sufficient absorption to occur. Absorption is a major factor to understand during formulation development and several strategies can be used to optimise this, including permeation-enhancing agents, mucolytic agents, mucoadhesive agents, in situ gelling agents and drug carrier technologies (Table 3). Mucoadhesive nasal gels are the most prominent non-invasive dosage forms through which a drug can reach systemic circulation directly, avoiding the firstpass effect and enhancing the underlying bioavailability of the drug.6

Agent

Action

Examples

Permeation-enhancing agents

Help to increase the transport of proteins and peptides across the nasal membrane by several modes of action

n-dodecyl beta-D-maltoside (Neurelis’s Intravail), surfactants e.g. polysorbates and lecithin

Mucolytic agents

Enhance nasal absorption

N-acetyl-L-cysteine (NAC)

Mucoadhesive / bioadhesive agents

Enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome

HPMC, carbopol 934 and sodium alginate

In situ gelling agents

Non-Newtonian fluids – free flowing when being mixed or sprayed but then forming a thick gel following actuation

Avicel RC591 (DuPont)

Drug-carrier technologies

Agents that enhance absorption through encapsulation or surface modification

liposomes, emulsions, nanoemulsions, nano/micro particles

Table 3: Potential formulation agents. www.ondrugdelivery.com

Intertek Melbourn

Making use of drug-carrying technologies, or technologies which modify the inhaled particle surface with agents that enhance their absorption, is a strong formulation strategy, provided that structural integrity can be maintained. For example, spraydried, polymer-coated liposomes composed of soy phosphatidylcholine and phospholipid dimyristoyl phosphatidylglycerol coated with alginate, chitosan or trimethyl chitosan demonstrate increased penetration of the liposomes through the nasal mucosa compared with uncoated liposomes when delivered as a dry powder.7 Introduction of agents at the structural level – for example, enzymeinhibiting agents – should be evaluated for additive activity or enhanced activity over and above the activity of the biologic on its own.

Attribute

Characteristics

Analytical Method

Comparative physiochemical & structural characterisation

Primary sequence confirmation

Peptide mapping approach (LC-MS/MS) ) covering full sequence confirmation, PTMs information (if applicable) and confirmation of di-sulphide (if peptide contacts cysteine), N/C terminus profiling

N-terminal sequence

Edman degradation

Free thiol determination

Ellman’s reagent

Amino acid composition

Amino acid analyser/HPPLC

Intact mass analysis

MALDI TOF/LCMS/ESI MS

High order structure

CD (near, far and thermal denaturation), FTIR, DSC, NMR -1D (1H & C13), 2D (TOCSY & NOESY), fluorescence spectroscopy, HDX

Optical purity

GCMS

Chiral confirmation (typically for peptides)

GCMS/LCMS

Oligomer/aggregation

UV-SEC-MALS, SV-AUC, DLS, SDS-PAGE, CE SDS

Charge variant profiling

iCIEF/IEX

Peptide-related impurity profiling

UPLC/HPLC- HR-MS/MS, RP-HPLC

Cell-based assay/immunoassay

In vitro cell-based method, based on the intended mode of action of the protein/peptide

TESTING In regulatory terms, inhaled and nasal biologics will require characterisation as per ICH Q6B, as well as the specific respiratory testing outlined in documents such as the EMA “Guideline on the pharmaceutical quality of inhalation and nasal products” (June 2006) or the US FDA “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products – Chemistry, Manufacturing, and Controls Documentation” (July 2002). Testing programmes should aim to both fully characterise the biological entity and establish whether the device delivery mechanism (e.g. actuation) has adversely affected parameters, including structure, purity (aggregation, fragmentation, etc.) and the activity (potency), in line with the ICH Q6B guidance. Nasal products also require specific testing to assess delivered dose uniformity from the device and the droplet/particle size of the drug emitted.

Impurity profiling

Biological activity

Table 4: Analytical methods to be considered in relation to development of a nasal protein or peptide product. Protein structures have limited stability and can easily unfold under only mild stress. Aggregation, where the protein selfassociates, is one of the most common issues, whereas fragmentation, deamidation, hydrolysis, oxidation, isomerisation, succinimidation, deglycosylation, disulphide

bond formation/breakage and other crosslinking reactions can all play their role in the stability of the biologic active. Table 4 illustrates the scope of tests required to determine critical quality attributes for protein or peptide therapeutics, which includes mass spectrometry (Figure 2).

CONCLUSION Intranasal is a promising route for biologic administration, which is reflected in the growing number of marketed products treating chronic diseases, as well as a large number of clinical trials currently in progress, particularly those focused on development of a treatment for the respiratory illnesses caused by SARS-Cov-2 infection or of vaccines. The nasal route of drug administration offers the potential to improve the delivery of biologics, even for very complex molecules such as antibodies. However, strategic formulation is required to make this a reality.

Figure 2: Mass spectrometry is a key analytical tool for the characterisation of biologics.

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Intertek Melbourn

A FOCUS ON PEPTIDES As peptides offer greater efficacy, safety and tolerability in humans compared with small molecules, and are also, due to their smaller size, better able to penetrate cell membranes compared with proteins, peptides have emerged as potential drug candidates for both therapeutics and vaccines against covid-19. Overall, the development pipeline is robust, with more than 100 peptides in late-stage clinical development and more than 200 in the preclinical stage, with

INTERTEK SOLUTIONS The recent expansion at Intertek’s Centre of Excellence for Inhaled and Nasal Drug Development in Melbourn (UK) has focused on new, powerful analytical strategies, integrated with formulation, stability and clinical trial material manufacturing to drive understanding of clients’ products and processes, enabling clients’ key decisionmaking activities throughout the product development life cycle. The Intertek team supports the design and optimisation of formulations for biologics or small molecules, powders, capsules, liquids, solids and semi-solids for inhaled, nasal, nebulised, pressurised and topical drug formulations. It delivers focused development strategies from an early stage which can be tailored to new chemical entities (NCEs) or generic products, from feasibility studies through to development support, Phase I and Phase II clinical trials, scale-up and transfer to commercial manufacturing. Intertek’s expertise helps accelerate project timelines and includes pre-formulation, excipient-API compatibility assessment and optimisation, physicochemical testing, formulation screening, lab-scale formulation and accelerated stability studies to achieve the desired product characteristics. It offers a broad range of analytical capabilities, including protein structure, physico-chemical properties characterisation and potency alongside solubility assessment, dissolution, solid state characterisation, particle morphology (Malvern Morphologi 4 ID), forced degradation and stability screening, in order to select the optimal development candidates. With a holistic approach to service provision, including raw material quality control, scale-up, pilot-scale batch Copyright © 2020 Frederick Furness Publishing Ltd

intranasal delivery being explored for many candidates. Within this pipeline, over 20 peptides are being assessed to address the recent global outbreak of covid-19/SARS-CoV-2 infection, including 15 synthetic peptides.8 Studies on the intranasal application of peptides have explored these candidates, either pre- or post-challenge with coronavirus, with outcomes that suggest these may have both prophylactic and therapeutic potential against SARS-CoV-2 infection.9

manufacturing and testing, GMP clinical batch manufacturing, stability storage and impurities testing, as well as release testing with qualified person (QP) release, Intertek offers a one-source solution for material supplies for use in Phase I and II clinical trials. The company understands the need to invest time to establish rugged methodology with a focus on identifying and controlling critical quality attributes as an integral part of product development. Its experienced scientists deliver analytical programmes to support all stages of development for both innovative and generic products, as well as maintaining involvement in the development of new and improved techniques and technologies.

ABOUT THE COMPANY With nearly 30 years of experience in supporting clients’ orally inhaled and nasal drug product development, Intertek Melbourn provides product performance testing, method development/validation, stability, CMC support, formulation development and clinical manufacturing capabilities. Intertek’s network of more than 1,000 laboratories and offices and over 46,000 people in more than 100 countries delivers innovative and bespoke assurance, testing, inspection and certification solutions for its customers’ operations and supply chains across a range of industries worldwide.

REFERENCES 1. Schwarz B, Merkel OM, “Nose-tobrain delivery of biologics”. Ther Deliv, 2019 Vol 10(4), pp207–210. 2. Darshana S, June S, “Nasal Delivery of Proteins and Peptides”. Glob J Pharmaceu Sci, 2017, Vol 1(4), 555569.

3. Grassin-Delyle S, Buenestado A, Naline E et al, “Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids”. Pharmacol Ther, 2012 Vol 134(3), pp 366–379. 4. Fromer LM, Ortiz GR, Dowdee AM, “Assessment of Patient Attitudes About Mometasone Furoate Nasal Spray: The Ease-of-Use Patient Survey”. World Allergy Organ J, 2008, article number 156. 5. Ward D, “Optimising Nasal Drug Products for Systemic Delivery”. ONdrugDelivery Magazine, Issue 106 (Apr 2020), pp 56–59. 6. Basu S, Maity S, “Preparation and characterisation of mucoadhesive nasal gel of venlafaxine hydrochloride for treatment of anxiety disorders”. Indian J Pharm Sci, 2012, Vol 74(5), pp 428–433. 7. Chen KH, Di Sabatino M, Albertini B et al, “The effect of polymer coatings on physicochemical properties of spray-dried liposomes for nasal delivery of BSA”. Eur J Pharm Sci, 2013, Vol 50(3-4), pp 312–322. 8. “Global Peptide Therapeutics Market, Dosage, Price and Clinical Trails Insight 2018–2024”. Research and Markets, September 2018. 9. Xia S, Liu M, Wang C et al, “Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion”. Cell Res, 2020 Vol 30(4), pp 343–355.

ABOUT THE AUTHOR David Ward is the Formulation and Manufacturing Lead for Intertek Melbourn. He has worked in the pharmaceutical and device development sectors for over 20 years across innovative pharma companies and device design and product development, specialising in formulation, analysis and clinical production approaches for orally inhaled and nasal drug products. He has worked across many device types including pressurised metered dose inhalers, dry powder inhalers, nasal products and nebulisers.

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Nemera

THE UNTOLD STORY OF NEMERA’S INHALATION FRANCHISE In this article, Raphaële Audibert, Global Category Manager, Inhalation & Dermal, and Niyati Sapatnekar, Global Communications Manager, both of Nemera, tell the story of the company’s journey from contract manufacturer to end-to-end inhalation partner.

Based on an article that originally appeared on the Nemera website in October 2020. Imagine the sheer joy and excitement of a child running towards an ice cream truck on a hot sunny day or an athlete as he crosses the finish line to win a sprint. Sounds terrific, right? But did you know that around 800 million people1 around the world might not feel this joy because they suffer from respiratory disorders – notably, asthma and chronic obstructive pulmonary disease (COPD). In simple terms, asthma is a medical condition that makes breathing difficult by causing the air passages to become narrow or blocked, especially during an asthma exacerbation. This, in turn, leads to wheezing, coughing, shortness of breath and chest tightness. Asthma is thought to be caused by a combination of genetic and environmental factors. For example, based on what we know about covid-19, people suffering from asthma might be more susceptible to severe illness. Under such circumstances, care and treatment options for these patient populations become all the more urgent. Unlike many other medical conditions, there is no cure for asthma. On the brighter side, medications help prevent exacerbation and attenuate the symptoms. COPD is another debilitating disease characterised by long-term breathing problems and poor airflow. The most common cause of COPD is tobacco smoking. Diagnosing

“Nemera has been instrumental in the inhalation space for more than 20 years.” 28

COPD is a challenge as most people do not realise they have it and do not reveal their symptoms to their doctors. The breathing problems tend to worsen over time and can limit an individual’s day-to-day activities.

UNMET MEDICAL NEEDS Although asthma and COPD are long-term conditions with no permanent cure, the symptoms can be controlled with the right treatment. The oldest and simplest way to treat lung diseases is with inhalation therapy. This is proven by the fact that more than one billion inhalers2 are sold globally every year. Moreover, these pulmonary conditions are expected to rise with the increasing elderly population, air pollution, climate change and evolving lifestyles. There are still several unmet medical needs in this space and poor adherence remains a big challenge. Adherence in reallife studies varies from 8% to 73%.3 This challenge stems mainly from improper use of inhalation devices, as well as lack of learning and training for those who handle these devices. A potential way forward could be the involvement of digital in the treatment journey of these patients – a connected device that reminds them to take their medication, for example, or warns them of an increase in pollution levels to ensure they are well equipped with their treatment.

THE JOURNEY FROM CONTRACT MANUFACTURING TO AN END-TO-END PARTNER Thanks to its robust manufacturing capabilities, coupled with outstanding

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Raphaële Audibert Global Category Manager, Inhalation & Dermal T: +33 6 76 25 13 02 E: raphaele.audibert@nemera.net

Niyati Sapatnekar Global Communications Manager T: +33 6 89 31 87 33 E: Niyati.sapatnekar@nemera.net Nemera 20 avenue de la Gare 38292 - La Verpillière France www.nemera.net Copyright © 2020 Frederick Furness Publishing Ltd

Nemera

Figure 1: A Nemera production line.

“Nemera has significantly developed its injection, moulding and assembly capabilities over the last few years to improve speed and on-line control. It has added electronic devices to its portfolio and shares best practices within its different franchises.” quality, Nemera has manufactured over a billion inhalers to date. Approximately 20 million patients rely on inhalers manufactured by the company every day. Historically known for contract manufacturing – which essentially means industrialisation of an already developed device – Nemera is now recognised as a holistic partner for inhalers. Nemera’s journey from a contract manufacturer to an end-to-end partner in inhalation is worth exploring. Nemera set foot in the inhalation space with Diskus for GlaxoSmithKline in 1998. Today, the form and purple colour of Diskus, among others in the range, are a reference and a mark of trust across the world. This first success then snowballed into other collaborations with blockbusters in the pharma industry and generic players that specialise in inhalation (Figure 1). Copyright © 2020 Frederick Furness Publishing Ltd

More than 1,500 people are dedicated to industrialisation and manufacturing at Nemera to make sure the company responds to small- and large-scale manufacturing needs of customers with precision. Thanks to its robust manufacturing capabilities, coupled with outstanding quality, it has manufactured over a billion inhalers to date. Approximately 20 million patients rely on inhalers manufactured by Nemera every day.4 Numbers say a lot but they don’t tell the whole story. Nemera’s people are driven by the aim of putting patients first. The end user of its products is a person who has trouble breathing or undertaking simple daily chores. The fact that its devices help these people motivates employees to learn and improve constantly. Nemera has significantly developed its injection, moulding and assembly capabilities over the last few years to improve speed and on-line control.

It has added electronic devices to its portfolio and shares best practices within its different franchises. For example, it is exploring how human factor studies and user-design experiences in its parenteral franchise can be applied within its inhalation franchise. Nemera’s early contract manufacturing included primarily dry powder inhalers (DPIs). DPIs can be preloaded with the medication(s) or a patient can load them with capsules as the dose-holding system, prior to use. A single dose of the medication is loaded and ready to be inhaled, for example, by sliding a lever, twisting a part of the device or, in the case of capsule devices, pressing buttons to pierce the capsule. Patients simply take a deep breath while their lips are sealed around the mouthpiece of the inhaler, and the dose is delivered. Then came actuator and dose counters for pressurised metered dose inhalers (pMDIs). These devices consist of an aluminium canister of medication covered by a valve fitted into a plastic body with a mouthpiece (the actuator). Each dose is delivered by pressing the canister into the actuator while inhaling through the mouthpiece. Sometimes, a dose counter can be added or integrated into the system. Inhalation devices are often complex because the inspiratory flow is linked to device resistance. In DPIs, for example,

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Nemera

Figure 2: Cloud solutions can help with data analysis to improve patient outcomes.

and services across ophthalmology, nasal, inhalation, dermal, transdermal and parenteral delivery. Nemera’s vision is to be the most patient-centric drug delivery device company. The company always puts patients first, providing high-quality solutions that have a demonstrable impact on patients’ health. Nemera’s Insight Innovation Center, with offices in North America and Europe, provides consultative services to support clients’ overall device strategies. Providing user research, human factors, user experience design, and design for manufacturing, the Insight Innovation Center helps customers navigate their device strategy for both novel and platform solutions. Users are at the centre of everything Nemera does in its efforts to always put patients first.

REFERENCES

“Nemera is part of the Cupido project, which aims to tackle cardiovascular disease by developing inhalable nanoparticles that can deliver a therapy directly to the diseased heart.” a patient’s breathing capacity is critical in generating the desired therapeutic outcome as the dispersed powder needs to be broken into particles of the right size and be deposited appropriately into the lungs. The best way of addressing these complexities is through early-stage research. Nemera’s innovation team works extensively on understanding the needs of patients and doctors – and fulfilling pharmaceutical requirements – so that the design it develops aims to resolve their issues. This also includes anticipating the needs of the future. Thus, from early-stage concept development to manufacturing, Nemera is a holistic partner in inhalation.

INHALERS OF TOMORROW Nemera’s inhalation franchise stands on a solid foundation. It learns from the past, acts in the present and builds for the future. The company’s ambition is to participate more and more in discussions around the inhalers of tomorrow: striving to ensure that its research takes into account sustainability and environment-related factors, evolving patient needs, increasing preference for digital and more. Nemera embeds digital organically. It has developed electronic devices that are tailored to enhance the patient experience to facilitate treatment 30

adherence. These smart devices are capable of monitoring drug dosages for patient safety. In addition, Nemera proposes cloud solutions to illustrate how the data generated can be analysed for the best outcomes. This will help extend its digital offering in inhalation (Figure 2). Nemera is part of the Cupido project, which aims to tackle cardiovascular disease by developing inhalable nanoparticles that can deliver a therapy directly to the diseased heart. The EU-based consortium – composed of six academic research groups, five SMEs, two industries and one pharmaceutical company – gathers a vast array of expertise and joins cutting-edge research with preclinical experience and industrial manufacturing. Nemera’s role in the consortium is to develop the inhaler that administers the nanoparticles to the diseased heart. What we do today has a long-lasting impact on our future. And the future is full of unexplored opportunities and hope.

ABOUT THE COMPANY Nemera is a world leader in the design, development and manufacturing of drug delivery devices for the pharmaceutical, biotechnology and generics industries. It offers a comprehensive portfolio of products

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1. “The Global Asthma Report 2018”. National Center for Biotechnology Information. 2. MIDAS & Analytics Link Databases, IQVIA, and Internal Nemera Data 3. Chrystyn H et al, “Real-life Inhaler Adherence and Technique: Time to get smarter!”. Respir Med, 2019, Vol 158, pp 24–32. 4. Internal Nemera Data.

ABOUT THE AUTHORS Raphaële Audibert holds a biomedical engineering degree from ISIFC (Besançon, France). She has worked in the medical device industry as a project manager for five years, where she led the development of a surgical instrument set for neurosurgery. Ms Audibert joined Nemera in 2016 as Category Manager for Inhalation & Dermal. Since then, she has helped identify the needs of tomorrow and in building the franchise strategies. Niyati Sapatnekar holds two Masters degrees, including communications, from Sciences Po (Rennes, France). She believes that focusing on healthcare communications is the best way to nurture her passion for language, science and people. At Nemera, her goal is to support the vision, mission and ambition of the company through engaging and impactful communications.

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Aptar Pharma

HOW EMOTIONAL INTELLIGENCE IS DRIVING IMPROVEMENTS AND MEETING THE CHALLENGES IN PULMONARY DRUG DELIVERY In this article, Howard Burnett, Vice-President, Global Account Management, & Head of Global Pulmonary Category at Aptar Pharma, explores how emotional intelligence can foster partnerships that have the potential to drive advances in understanding and improving patient outcomes, and presents the case for a single-source, turnkey approach to pulmonary solution development. Everyone who works in the pulmonary drug development space recognises what a complex subject it is, comprising several interconnected disciplines that, right now, aren’t actually connected. This is simply because, to date, there hasn’t been one partner that can offer the breadth of experience and the depth of expertise needed by pharmaceutical clients. Add to that the present challenge of switching propellants from the currently used hydrofluoroalkanes (HFAs) to newer, more environmentally friendly alternatives,

“Finding solutions demands a relationship with the necessary depth and understanding, ideally one where all parties achieve more by synergistically working and sharing together; one where the whole is far greater than the sum of its constituent parts.” Copyright © 2020 Frederick Furness Publishing Ltd

and the pulmonary drug delivery space looks even more fragmented and tricky to navigate. As a market leader in respiratory drug delivery device solutions, Aptar Pharma has addressed these challenges head on. Aptar recognises that the only sustainable way to connect the disciplines involved in pulmonary drug device development and overcome the sector’s difficulties is to begin with an evolution in culture and behaviour that drives continuous improvement. Aptar is committed to an open, trusting and collaborative partnership approach to solving the challenges of reduced environmental impact and improved patient outcomes.

COMPLEX SKILL SETS TO ANSWER COMPLEX CHALLENGES The most successful innovation journeys begin by addressing an unmet patient need. However, in pulmonary drug development, the pathway from here to there is far from straightforward. From API development and deposition modelling to device design and regulatory approval, there is a series of interconnected stages that must be aligned and balanced in order to arrive at the ultimate goal: delivering a safe and

Howard Burnett Vice-President, Global Account Management, & Head of Global Pulmonary Category T: +33 23209 1558 E: Howard.Burnett@aptar.com Aptar Pharma Route de Falaises 27100 Le Vaudreuil France www.aptar.com/pharmaceutical

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Aptar Pharma

effective product to market quickly and economically, all while reducing risk. Within this competitive context, with its fine margin between success and failure, there is also the need to respond to important external issues, ranging from climate change to covid-19. Answering these challenges requires a mix of the right skill sets and, while pharmaceutical companies will have core in-house competencies to varying degrees, it is a situation that encourages sourcing a range of technical capabilities and specialist expertise from supporting stakeholders. If success is rooted in collaboration, Aptar believes it can only truly be unlocked through real partnerships that go beyond a project. There is a breadth of issues at play in the mature yet fastchanging pulmonary medication market. Therefore, finding solutions demands a relationship with the necessary depth and understanding, ideally one where all

parties achieve more by synergistically working and sharing together; one where the whole is far greater than the sum of its constituent parts. In short, a relationship where 1+1 > 2 (Figure 1).

DEFINING THE RELATIONSHIP Great partnerships – both personal and professional – are always admired. In business, this reflects the fact that they can be difficult to cultivate, since at their core there is traditionally a client/supplier dynamic that may not be truly balanced. So, what are the qualities that make for a genuinely successful partnership? Do they represent more than a simple client/supplier dynamic? Should success be defined purely by contractual obligations and transactional exchanges? With the potential for a range of answers to these questions, it is easy to see how the idea of a partnership remains open

Figure 1: To achieve real success in the pulmonary market, pharma companies need a relationship with a device partner where the relationship is greater than the sum of its parts; where 1+1 > 2.

THE SECRET TO PARTNERSHIP SUCCESS A key ingredient for facilitating success is for both parties to bring a higher degree of emotional intelligence (EQ) to the table. EQ acts as a catalyst for introducing the desired parameters of clear communication, openness and mutual trust. The concept of EQ was first defined by scholar Joel Davitz and clinical psychologist Michael Beldoch in their 1964 book “The Communication of Emotional Meaning” and was later popularised by journalist Daniel Goleman in “Emotional Intelligence”, a 1995 international bestseller.

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to interpretation and, in turn, how there is a very real risk of two parties being engaged in a relationship where they are misaligned in terms of culture, values, objectives and behaviours. Such mismatched relationships can be breeding grounds for miscommunication and potential friction, causing what would be otherwise simple project obstacles to escalate into more significant barriers that inhibit success. Aptar Pharma believes that the nature of today’s pharmaceutical market means that a true partnership approach is fundamental to successful drug development. By sharing the same objectives and being emotionally and intellectually invested in each other’s success, innovation and productivity really can flourish. And, by embracing true partnership, processes can be accelerated, focus and control can be maintained and demonstrable progress can be realised.

www.ondrugdelivery.com 34

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EQ primarily refers to an individual’s ability to recognise emotion in themselves and others, and to use that information to help guide their thinking and behaviour, adapt to environments, and achieve certain goals (Figure 2). These are qualities we typically associate with people, but organisations also have the potential to display EQ in the context of a partnership. This is particularly true in companies whose collective values and behaviours manifest themselves in an identifiable organisational culture that not only guides internal decision making and influences how employees interact with others, but also shapes how the business responds to market forces. Aptar prides itself on having such a programme, called “Organizational Effectiveness Development” (OED), which helps drive and guide the company culture across a variety of themes important to the company’s relationships, such as leadership, collaboration and communication. Within pulmonary drug development, the influence of a product’s environmental impact is becoming ever more significant. Growing awareness of climate change has driven legislators to implement guidance and regulation aiming to push the industry towards greater environmental sustainability, and stakeholders within the supply chain to place increasing emphasis on the development of products with a lower global-warming potential (GWP).

WORKING TOGETHER ON CARBON REDUCTION A major milestone in this journey was the signing of the Montreal Protocol in 1987, which phased out the consumption and production of chlorofluorocarbons (CFCs), which are known to be both greenhouse gases and harmful to the ozone layer. Given the dominant position of CFCs as a pressurised metered dose inhaler (pMDI) propellant, this demanded an immediate recalibration by the pharmaceutical industry towards hydrofluoroalkane (HFA) propellants. As such, the first HFA-based salbutamol product was launched in the UK in 1995. Today, with the manufacture and sale of CFC-based products now banned entirely, attention has turned to the carbon impact of the broader collective group of fluorinated gases (F-gases), which includes HFAs. This presents the industry with the next challenge in its carbon-reduction journey. Copyright © 2020 Frederick Furness Publishing Ltd

Aptar Pharma

Figure 2: Whilst the value of a potential partner’s technical “know-how” is very well established in the pharma industry, it is also important to find a partner with the emotional intelligence to understand and gel with a pharma company’s culture and values, to have the “know-you” factor.

“Building a more sustainable future for pMDIs by transitioning to more environmentally friendly propellants, such as HFA152a, is a top priority for Aptar Pharma.” Therefore, there is a continuing exploration of alternative options, such as HFO 1234ze and HFC 152a (1,1-Difluoroethane), whose promise as a pMDI propellant must be balanced with available data on its safety. In the wake of the Kigali amendment to the Montreal Protocol in 2016, more than 60 countries across the globe are committed to a managed phasing-down of hydrofluorocarbon (HFC) gases. In addition, the member states of the EU are aiming to cut F-gas emissions by two-thirds by 2030 compared with 2014 levels.1 While the long-term environmental benefits are clear, these deadlines will have short-term implications that require an EQ response from companies that understand each other, value each other’s contribution and have a shared vision of what success looks like.

SUPPORT FROM DESIGN TO COMMERCIALISATION Successful partnerships are crucial for pharmaceutical companies looking to overcome this significant challenge. It requires a partner with pulmonary delivery expertise that might begin simply with elastomers and valves, but whose

competencies extend into the far reaches of a complex process, incorporating formulation science, device design, testing and regulatory approval. There is a requirement to work side by side, with existing in-house capabilities complemented by a partner with an end-to-end service offering that encompasses all the required aspects to manage the device pathway and optimise lifecycle management. Building a more sustainable future for pMDIs by transitioning to more environmentally friendly propellants, such as HFA152a, is a top priority for Aptar Pharma. The company is bringing its partnership philosophy to pharmaceutical organisations in pursuit of this shared objective, drawing on the strength of its research and development laboratories and filling capabilities in Le Vaudreuil (France). Aptar’s collaborative work with clients and companies, such as fluoroproducts specialist Koura, is focused on screening Aptar Pharma metering valves across multiple model formulations and optimising new valve configurations. It has shown that the distinct properties of HFA152a, such as its low liquid density, are not an obstacle to working with suspensions.

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Aptar Pharma

RISING TO RESPIRATORY CHALLENGES Carbon-reduction strategies are not the only area where partnerships driven by EQ and innovation are addressing needs in the pulmonary space. Respiratory diseases continue to present a major threat to global health; more than one billion people suffer from either acute or chronic respiratory conditions. Chronic obstructive pulmonary disease (COPD), asthma, acute lower respiratory tract infections, tuberculosis and lung cancer are among the most common causes of severe illness and death worldwide.2 For many of these diseases, their health burden is on the rise, placing greater urgency on the need to develop therapies that can ease suffering among patients. Inhaled drug delivery devices present several major advantages in addressing these unmet needs, such as improved compliance, the ability to provide high drug payloads with targeted delivery and the possibility of minimising associated packaging. Aptar Pharma’s expertise in this area was further enhanced following its acquisition of Nanopharm in 2019, a move that introduced SmartTrack™ to Aptar’s offering to help both de-risk and accelerate the pathway for orally inhaled and nasal drug products (OINDP). The perennial challenge of better assuring patient adherence and compliance to medication regimes continues to be addressed with the accelerated adoption of digital health solutions – an area where Aptar has been at the forefront for several

“Aptar fosters a culture that encourages and attracts people with a level of EQ that enables it to forge strong and successful partnerships.”

years, now having integrated and add-on devices available for a range of pMDI technologies. The recent acquisition of Cohero Health, a digital therapeutics company transforming respiratory disease management for asthma and COPD, further reinforces Aptar’s drive to improve respiratory care, reduce avoidable costs and optimise medication adherence.

HOW EQ DRIVES RETURN ON INVESTMENT Given the prioritisation and fast tracking of covid-19 treatments, even greater value is now placed on having robust relationships with reliable, knowledgeable partners who can help jointly overcome development hurdles and accelerate safe products to market. At the same time, the more cynical may ask, “What’s in it for me?” The philosophy of a closer partnership approach may be advocated by a supplier, but some clients will rightly question whether moving from the transactional to a more multidimensional relationship delivers tangible positive outcomes. In Aptar’s experience, the benefits are clear. The company fosters a culture that encourages and attracts people with a level of EQ that enables Aptar to forge strong and successful partnerships. As a result, Aptar has enjoyed a solid, decades-long relationship with one of the world’s most successful pharmaceutical companies, and the value creation derived from the shared approach has been consistently impressive. Together, the companies have enabled and de-risked projects in much shorter timeframes, whilst developing valuable IPs. They have created solutions for unmet patient needs, developing delivery solutions for a range of payloads in a wide range of therapeutic areas. Furthermore, they have built a 360° data lake that shares intelligence and insight to support the culture of continuous improvement. All this with a consistent defect rate of just 0.02% in the hundreds of millions of devices Aptar delivers every year.

Aptar firmly believes that the trend towards more sophisticated, deep-rooted partnerships is set to continue. For Aptar, two-dimensional supply-and-demand agreements must evolve to become threedimensional, multi-layered collaborations to manage the increasingly complex, interconnected landscape of pulmonary drug development. For pharmaceutical companies, the challenge is not only in finding a partner with the right capabilities, but one with the shared ambition and emotional intelligence to ensure both parties succeed together.

ABOUT THE COMPANY For pharma customers worldwide, Aptar Pharma is the go-to drug delivery expert, providing innovative drug delivery systems, components and active packaging solutions across a wide range of delivery routes including nasal, pulmonary, ophthalmic, dermal and injectables. Aptar Pharma Services provides early-stage to commercialisation support to accelerate and de-risk the development journey. With a strong focus on innovation, Aptar Pharma is leading the way in developing connected devices to deliver digital medicines. With a global manufacturing footprint of 14 manufacturing sites, Aptar Pharma provides security of supply and local support to customers. Aptar Pharma is part of AptarGroup, Inc. (NYSE:ATR).

REFERENCES 1. “Regulation (EU) No 517/2014 of the European Parliament and of the Council of 16 April 2014 on fluorinated greenhouse gases and repealing Regulation (EC) No 842/2006”. Official Journal of the European Union, 2014. 2. “The Global Impact of Respiratory Disease – Second Edition”. Forum of International Respiratory Diseases, 2017.

ABOUT THE AUTHOR Howard Burnett is Vice-President, Global Account Management, and Head of Global Pulmonary Category for Aptar Pharma. He has more than 30 years of experience in the field of inhalation devices for treatment of respiratory conditions. Mr Burnett has a background in mechanical engineering, having studied particle physics as part of his bachelor’s degree from the University of York (UK). His postgraduate qualifications include management studies and education. He has held management positions in R&D, engineering, operations, marketing and business development.

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Working daily to improve the health of our patients and our planet

As the market leader in pMDI valve technology for asthma and COPD, Aptar Pharma is committed to improving the environmental impact of our products and ensuring our devices are safe and effective. Thatâ&#x20AC;&#x2122;s why we are actively engaged in defining the next generation of pMDIs, finding more sustainable solutions with alternative propellants that align with our sustainability commitments as well as those of our partners and their patients. To find out more about how Aptar Pharma is advancing pMDI technologies, please visit www.aptar.com/pharmaceutical /delivery-routes/pulmonary/

Delivering solutions, shaping the future.

Kindeva

COLD FILLING VERSUS PRESSURE FILLING: THE CASE FOR VERSATILE, FULLY INTEGRATED CDMOs In this article, Steve Haswell, Process Development and Tech Transfer Team Leader at Kindeva Drug Delivery, compares the two main processes for manufacturing pressurised metered dose inhalers – and examines the value for pharmaceutical companies of working with contract development and manufacturing organisations that have expertise in both processes. Kindeva Drug Delivery traces its legacy back to the development of the world’s first pressurised metered dose inhalers (pMDIs) in 1956. In more recent decades, the inhalation industry has seen diversification of device formats ranging from the proliferation of dry powder and soft mist inhalers to the introduction of connected inhalers. While there is much discussion on the relative advantages and disadvantages of different device types, the pMDI continues to be a critically important device. Although pMDIs can appear to be similar from a patient’s perspective – with use and technique being largely the same from one pMDI product to another – there are important differences among pMDI products. Formulations for pMDI products can vary quite significantly, with different chemical and physical properties. This variation affects not only how these drug products are formulated but also how they are manufactured. There are two predominant processes for manufacturing pMDIs: cold filling and pressure filling. This article provides a comparison between these two processes.

It also examines the value – from the perspective of a pharmaceutical company – of working with contract development and manufacturing organisations (CDMOs) that possess capabilities and expertise in both processes. This article also reflects on the introduction of quality-by-design (QbD) initiatives and emphasises the importance of CDMOs with integrated, end-to-end capabilities and expansive cross-functional expertise.

pMDI MANUFACTURING OVERVIEW At a high level, the pMDI manufacturing process can be segmented into five stages: propellant batching, concentrate preparation, canister filling, post filling and equipment cleaning (Figure 1).1 Because standard pMDI propellants are gaseous at ambient temperature and pressure, they must be liquefied before manufacturing equipment can process them and effectively fill the pMDI canisters. In the propellant batching phase, the propellants are liquefied by either lowering the temperature within a refrigerated vessel (used in a cold-filling

“In the current landscape of drug development, in which pharmaceutical companies are investing in dual and triple combination products that contain multiple APIs, the selection of pMDI manufacturing process is crucial.”

Steve Haswell Process Development and Tech Transfer Team Leader E: steve.haswell@kindevadd.com Kindeva Drug Delivery Charnwood Campus 10 Bakewell Road Loughborough LE11 5RB United Kingdom www.kindevadd.com

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Kindeva

programme and consider a variety of factors, including the equipment design and the toxicity of all the APIs, excipients and cleaning materials used on that equipment.

CONSIDERATIONS FOR COLD FILLING AND PRESSURE FILLING

Figure 1: Overview of the pMDI manufacturing process. process) or by increasing the pressure in a pressurised vessel (used in a pressurefilling process). Then, during the concentrate preparation stage, the API is combined with a liquid solvent or a propellant and then transferred to the batching vessel. Canister filling differs by cold-fill and pressure-fill processes and may be conducted in a single stage or in two stages. In cold-fill processes, the API or concentrate is pre-mixed with the propellant at a low temperature and then dispensed into empty pMDI canisters. A metering valve is then crimped into place. Importantly, formulation is not driven through the valve. In a single-stage pressure-fill process, the metering valve is pre-crimped onto the canister before filling. The formulation – API or concentrate pre-mixed with the propellant under pressure – is injected through the valve, into the canister. In a two-stage pressure-filling process, the concentrate is first dispensed into an empty canister, the metering valve is crimped into place and then the propellant is injected through the valve. More recently, in addition to the single- and two-stage processes, a dualfilling process has become available. Under this process, a concentrated formulation is dispensed through a pre-crimped valve, followed by the propellant using a single fill head. An advantage of the dual-filling technique is that the addition of trailing propellant through the valve helps to cleanse the API residue from the internal Copyright © 2020 Frederick Furness Publishing Ltd

pathway within each valve. This process is gaining popularity as the related process patents expire. Post-filling activities involve a series of in-process controls to challenge and test factors such as fill weight, crimp dimension, heat stress and function. Through-batch units can be sampled for product release testing. Finally, the equipment must be cleaned. Cleaning methods are developed, optimised and validated for each pMDI

In the current landscape of drug development, in which pharmaceutical companies are investing in dual and triple combination products that contain multiple APIs, the selection of pMDI manufacturing process is crucial. Pressure-filling techniques are best suited for solutions where the API is fully soluble in the final formulation.2 On the other hand, pressure filling can present challenges for suspensions where the API is not soluble. The challenge for pressure filling is particularly true with suspensions that have high powder loads. Pressure filling these formulations can create clogging of the valve and fill head as a result of the highly concentrated API. The dominant pMDI manufacturing process in the industry is the single-stage pressure-fill process. The prevalence of pressure filling is at least partially attributable to its operational accessibility. Despite some operational advantages, there are a myriad of factors that must be considered when selecting between coldand pressure-filling processes (Table 1). Both have advantages and disadvantages.

Cold Fill

Pressure Fill

Filling Speed per Unit

• Bespoke • Low number of fill heads

• Multi-head, off-the-shelf equipment available

Formulation Type

• Solutions or complex, high powder loaded suspensions

• Solutions to medium powder loaded suspensions

• Cold tolerant

• Stability in vessel • Accurate propellant top-up through batch

Valve Selection

• Fill into open can

• Fill through valve

Process Equipment

• Materials of construction (MOC) that will tolerate low temperatures

• MOC that will tolerate high pressure and provide effective sealing

Fill Weight Accuracy

• Important for accuracy of number of shots

• Same as cold fill in single-stage process •C ritical in two-stage process as final drug content is impacted

Unit Purge Requirements

• None

• Unit must be purged or vacuum crimped

Valve Equilibration & Gasket Swelling

• Begins later in process during spray testing

• Begins at start of filling process

Table 1: Considerations, advantages and disadvantages for filling processes. www.ondrugdelivery.com

Kindeva

Pressure filling may become more challenging for dual and triple combination products as they can have higher powder loading. To successfully pressure fill such formulations, manufacturers will need to select a valve that can withstand higher powder densities. Even with careful valve selection, the valves can be susceptible to clogging. Cold filling is not challenged in the same way, since the formulation is not injected through the valve during filling. While cold filling tends to be a more appropriate process for high powder load suspensions, it is not without its challenges. First, formulations must be tolerant to cold temperatures, since cold filling is performed at temperatures between -60°C and -50°C. If a formulation is at the edge of solubility, it may not be a good fit for cold filling, as the API may come out of the solution at low temperatures. Moreover, cold-filling equipment and pMDI components can be susceptible to water condensation or ice formation, which can result in moisture uptake.2 To avoid this, cold filling requires strict environmental controls.

THE IMPORTANCE OF CDMO VERSATILITY Based on these considerations, there is no single manufacturing process that is categorically best in every situation. Rather, the scientific literature urges that the selection of a manufacturing process should be a product-specific approach.2 This selection should not be strictly determined by the options that the manufacturer has available. Therefore, CDMOs with the equipment, capability and experience to provide both pressure filling and cold filling can offer an optimal approach and important advantage to their pharmaceutical partners. When Kindeva formulators begin working with a partner on the development of a new inhaled product, manufacturing considerations are discussed from the very first phases of the programme. As part of the feasibility stage, the Kindeva technical team evaluates both the pressurefilling and the cold-filling options. Kindeva scientists are able to deduce the optimal filling process early on. It is important to consider both processes in the feasibility stage. Since the suitability of the filling process is dependent on the product and the formulation, Kindeva’s ability to evaluate the suitability of both pressure-fill and coldfill processes during the early feasibility 40

“The optimal selection of a manufacturing process at the feasibility and development stages is extremely significant for pharmaceutical companies because of the potential impact this decision has on long-term product performance and quality.” stage, as well as the ability to scale the process to commercial production, enables alignment of the manufacturing process to the specificities of the client’s product. The optimal selection of a manufacturing process at the feasibility and development stages is extremely significant for pharmaceutical companies because of the potential impact this decision has on longterm product performance and quality. The choice of filling process can impact critical product quality attributes such as aerodynamic particle size distribution (APSD), delivered dose uniformity (DDU), canister content assay, fill weight and moisture.2 For example, with suspension formulations, a precise level of particle disaggregation is needed to attain the required APSD consistently. Additionally, regardless of which manufacturing process is selected, the volumes of concentrate and propellant must be carefully controlled, which traditionally has been more challenging in two-stage filling processes. These types of quality issues can ultimately impact the performance of the product at the patient level. Therefore, a CDMO that has the versatility to deploy a variety of manufacturing processes is in

“Quality must be designed into the product, requiring an understanding of the relationship between raw materials, formulation, process development and, ultimately, the performance of the product.”

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a better position to help reduce the risk of future quality issues that arise for their pharmaceutical partners.

THE VALUE OF END-TO-END CAPABILITIES Recent QbD initiatives, along with industry best practices, stipulate that quality must be designed into the product, requiring an understanding of the relationship between raw materials, formulation, process development and, ultimately, the performance of the product.3 In order to design a successful manufacturing process, it is beneficial to have cross-functional expertise, rather than specialised expertise in a single functional area. At Kindeva, every aspect of the business is engaged at the onset of the programme, with collaboration among global experts in formulation, analysis, device development, clinical trials, quality, manufacturing, regulation and marketing. This level of engagement is not only necessary to design an appropriate manufacturing process, it is valuable for designing a winning commercial strategy and high-performance product. It is important not to overlook the product’s commercial strategy when selecting a manufacturing process. Twostage filling processes are often difficult to scale up, have lower output rates and can present difficulties in repeatedly dispensing concentrate accurately – and therefore may be less preferable in large-batch situations.2 Moreover, it is valuable to work with CDMOs that have manufacturing capabilities and experience at a commercial level, not just at the bench scale. Some process risks may not be relevant at the bench or pilot scales but can manifest during scale-up and commercial manufacturing processes.2 These risks can be mitigated by evaluating process development with a commercial lens at the programme’s inception. Choosing a CDMO with a strong regulatory and clinical track record can be especially valuable. For customers that have identified the countries in which they want to market their product, it is important to involve the clinical and regulatory team as early as possible, so that they can provide valuable counsel as the programme develops. Early involvement of the regulatory experts supports the robustness of the regulatory strategy at the time of submission. Kindeva can provide this regulatory and clinical expertise based on its track record of product development, Copyright © 2020 Frederick Furness Publishing Ltd

Kindeva

scale-up and regulatory approval of both inhaled and transdermal products.

CONCLUSION Of the two dominant manufacturing processes for filling pMDIs – cold filling and pressure filling – neither is categorically superior. Rather, each strategy has benefits and the filling process should be selected primarily based on the physical properties of the individual formulation. Therefore, CDMOs should evaluate the suitability of both filling processes for their partners’ products. The evaluation and selection process exemplifies the value of choosing a CDMO that has the capability and experience to develop multiple types of manufacturing processes. The selection of a pMDI manufacturing process – from feasibility through to commercial supply – further illustrates the value of possessing end-to-end, crossfunctional capabilities. Kindeva engages every aspect of the business at every stage of development. This multifaceted expertise is leveraged to design a high-performance

product and develop a manufacturing process and regulatory strategy that will achieve the pharmaceutical partner’s commercial objectives and secure long-term supply of reliable products to patients in multiple markets.

US and the UK and employs approximately 1,000 people. The company has a long track record of industry firsts, including the first pMDI, the first drug-in-adhesive patch, the first breath-actuated inhaler and the first CFC-free pMDI and CFC-free nasal pMDI.

ABOUT THE COMPANY

REFERENCES

Kindeva Drug Delivery is a CDMO offering its partners integrated, end-to-end capabilities spanning formulation, product development, scale-up manufacturing and commercial manufacturing. Its full-service innovation offering covers: inhalation (pMDIs, dry powder inhalers, connectivity and nasal delivery); transdermal delivery (drug-in-adhesive systems and gel patches); and intradermal delivery (microneedles based on solid and hollow microstructures). Kindeva Drug Delivery has locations in the

1. Haswell S, “An approach to process development of pMDIs using cold fill and pressure fill technology”. Conference Presentation, DDL 26, 2015. 2. Vallorz E, Sheth P, Myrdal P, “Pressurized Metered Dose Inhaler Technology: Manufacturing”. AAPS PharmaSciTech, 2019, Vol 20, pp 177. 3. “Guidance for Industry Process Validation: General Principles and Practices”. US FDA, Jan 2011.

ABOUT THE AUTHOR Steve Haswell is a Process Development and Tech Transfer Team Leader at Kindeva Drug Delivery, based in Kindeva’s Loughborough (UK) research and development laboratory.

2021 EDITORIAL CALENDAR Publication Month

Issue Topic

January

Skin Drug Delivery: Dermal, Transdermal & Microneedles

Dec 17, 2020

January/February

Prefilled Syringes & Injection Devices

Dec 31, 2020

February

Novel Oral Delivery Systems

Jan 7, 2021

March

Ophthalmic Drug Delivery

Feb 4, 2021

March/April

Drug Delivery & Environmental Sustainability

Feb 18, 2021

April

Pulmonary & Nasal Drug Delivery

Mar 4, 2021

May

Delivering Injectables: Devices & Formulations

Apr 1, 2021

June

Connecting Drug Delivery

May 6, 2021

July

Novel Oral Delivery Systems

Jun 3, 2021

August

Industrialising Drug Delivery

Jul 1, 2021

September

Wearable Injectors

Aug 5, 2021

September/October

Drug Delivery & Environmental Sustainability

Aug 19, 2021

October

Prefilled Syringes & Injection Devices

Sep 9, 2021

November

Pulmonary & Nasal Drug Delivery

Oct 7, 2021

December

Connecting Drug Delivery

Nov 5, 2021

Materials Deadline

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Gerresheimer

DEVELOPMENT AND PRODUCTION OF THE RESPIMAT® REUSABLE INHALER HOUSING MODULE Here, Josef Schmid, Program Manager, Markus Müller, Development Engineer, and Nina Zielonka, Mould Engineer, all of Gerresheimer, discuss Gerresheimer’s recent work on developing the housing module for Boehringer Ingelheim’s new version of the Respimat® inhaler, including how design and creation of manufacturing equipment for the industrial scale-up took place in tandem with device design to meet the desired schedule. Recently, Gerresheimer was commissioned by Boehringer Ingelheim to develop and produce a housing module for the new generation of Respimat® inhalers (Figure 1). The new model is an environmentally friendly successor to the established Respimat ® inhaler, which can be successively loaded with up to six active agent cartridges, thus ensuring less waste and a considerably reduced CO2 footprint over the product lifecycle. Gerresheimer developed the housing module for the new inhaler and built the pre-series and series moulds, as well as the special-purpose machinery, for both pre-series and series production. Gerresheimer is also providing the scaled-up industrial production. The Respimat® inhaler is a firmly established product in the respiratory drug delivery market. Patients with chronic lung diseases, such as chronic obstructive

“One of the challenges Gerresheimer faced during product development and industrialisation was the need for the new inhaler to be immediately available in large numbers for its market launch. Therefore, it was necessary to immediately transition from the development phase to a robust, high-volume series production.”

Josef Schmid Program Manager E: josef.schmid@gerresheimer.com

Markus Müller Development Engineer E: markus.mueller@gerresheimer.com

pulmonary disease (COPD), use bronchodilation drugs on a daily basis to relieve their illnesses. Alongside the

Nina Zielonka Mould Engineer E: nina.zielonka@gerresheimer.com Gerresheimer Regensburg Oskar-von-Miller-Straße 6 92442, Wackersdorf Germany

Figure 1: Gerresheimer develops and produces the Respimat® reusable inhaler housing module. 42

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Gerresheimer

frequency of required use is a correspondingly high demand for inhalers, which usually need to be replaced once the active agent has been exhausted. To address this, Boehringer Ingelheim decided that the new version of the Respimat® would be reusable. In addition to being more environmentally friendly, the new Respimat® incorporates feedback from patients using the current model, including improving the inhaler’s ergonomics, via an extension of the housing, and making the dosage display more readable.

Figure 2: Cleanroom production in small batch production of Gerresheimer in Wackersdorf, Germany.

ROBUST DEVELOPMENT FOR A TIGHT PRODUCTION TIMELINE One of the challenges Gerresheimer faced during product development and industrialisation was the need for the new inhaler to be immediately available in large numbers for its market launch. Therefore, it was necessary to immediately transition from the development phase to a robust, high-volume series production. In technical terms, a reversible blocking mechanism had to be developed for the inhaler, without significantly changing the exterior design of the product and the valuable high level of recognition that goes with it. In order to meet such a demanding schedule, both the device-development phase and the creation of equipment for large series production were undertaken simultaneously. Another decisive factor for the success of the project was the availability of Gerresheimer’s own cleanroom for small series production,

“In order to meet such a demanding schedule, both the device-development phase and the creation of equipment for large series production were undertaken simultaneously.” which allowed for prompt testing of prototypes under real conditions (Figure 2). During development, a small-scale production foundation was first established using low-cavity moulds and semiautomated processes. On the basis of this foundation, the development of high-cavity moulds and fully automated processes for high-volume, large series production was undertaken immediately. By doing so, the development of the series equipment could be initiated ten months prior to

the planned design verification. A riskbased approach that ensured the systematic mastering of all risks pertaining to the device functions was used for the jump to large series production (Figure 3). Due to this robust development approach, along with the prescribed high functional density of the device, all functional tests for the design verification of the low-cavity moulds, and later those for the implementation of the high-cavity series moulds, were passed immediately.

Figure 3: High-volume line for the assembly of the Respimat® reusable inhaler housing module in a clean-room ISO class 8 in Pfreimd, Germany.

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Gerresheimer

inhaler, the device block requires a complex assembly process, for which an innovative assembly concept was formulated in a multi-stage process. This assembly process was initially realised in a semi-automatic assembly system and then transferred to an automated high-volume series machine. The immediate success of the acceptance run confirmed the chosen procedure.

“The size and complexity of the high-cavity moulds for large series production, which weigh up to three tons, were especially challenging.”

MOULDS OF EXTRAORDINARY COMPLEXITY The moulds for the development phase and series production were developed, produced, and optimised in Gerresheimer’s Technical Competence Center in Wackersdorf (Germany), which is home to its own mouldmaking facility. The size and complexity of the high-cavity moulds for large series production, which weigh up to three tons, were especially challenging. Gerresheimer used mould flow and finite element method calculations during mould development, as well as for the continuous improvement of the mould design and ensuring its long-life fatigue strength. Verification of the results took place on the basis of real long-life fatigue strength

experiments carried out on selected steel types. The start-up management of the moulds was secured with the help of KepnerTregoe analyses for the methodological, continuous improvement process. Work is currently being carried out on the creation and qualification of the third generation of successor tools.

ABOUT THE COMPANY Gerresheimer is a leading international partner to the pharmaceutical and healthcare industries. The company contributes to health and well-being with its range of glass and plastic products. Gerresheimer has a worldwide presence, with around 10,000 employees; locations in Europe, Asia and North and South America; and an annual turnover of around €1.4 billion (£1.3 billion). The company’s product offering includes insulin pens, inhalers, micro pumps, prefillable syringes, injection vials, ampules, bottles and containers for liquid and solid medications with sealing and safety systems, as well as packaging for the cosmetics industry.

INNOVATIVE AUTOMATION CONCEPTS Gerresheimer used the innovative XTS system from Beckhoff (Verl, Germany) for the first time for automating the module assembly for the reusable Respimat®. Here, products are transported on movers, which are moved across the transport area by freely configurable electromagnetic forces. As a key component of the reusable

Inhalation & Respiratory Drug Delivery Europe: Online 20 - 21 April 2021 | BST (UTC+1)

• 2-day Event • Virtual Congress & Exhibition

Discover novel case studies on the latest challenges and innovations in inhaled therapy formulation and drug delivery. Over 25 presentations focusing on emerging therapies and key issues in inhalation and respiratory drug development as well as the latest developments in inhalation devices and digital & connected health. This event will bring together leading experts in inhalation, respiratory, and nasal drug development & delivery science representing global pharmaceutical organisations, leading biotechnology companies, and internationally renowned academic and research organisations.

Agenda at a Glance

Formal and informal meeting opportunities oﬀer delegates the chance to discuss key solutions with leading service providers:

• Inhalation Drug Delivery

• Nasal Sprays

• Inhaled Dosage Forms

• Bioavailability

• Respiratory Drug Development

• Dry Powder Inhalers

• Connective Health, Smart Tech and AI

• Inhalation Formulation

• Analytical Chemistry

• Improving Patient Adherence and Dosing Technique With Product Design

• Respiratory Pharmaceutics

• Aerosols & MDIs

Inhalation Devices & Combination Products

• Aerosol Research & Development

• Novel Technologies For Pulmonary & Nasal Delivery

• Characterising Aerosol Dynamics • Particle Engineering • Inhaled Delivery Challenges & Solutions • Innovative Therapies for: COPD, Asthma, IPF, Cystic Fibrosis & COVID-19 • Case Studies on Alternative Therapeutic areas including: Inhaled Biologics, Vaccines, Antibodies & Insulin

500+ VPs, Directors & Senior Managers from leading life sciences companies and research institutions in the following ﬁelds and more:

Development & Formulation of Inhaled Therapies

• Modelling & Simulation In Inhalation

Who will be there?

• Innovative Development of Inhalation Devices Including: DPIs, MDIs, Generic Products

• Digital Health for Combination Products

• Inhalation Devices

• Challenges of Bringing Inhalation and Respiratory Products to the Market • Regulatory Pathways for Inhaled Therapies • Manufacturing Inhaled Medicines

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More Info |

Visit The Website: www.oxfordglobal.co.uk/formulation-delivery-series-uk-virtual/ Contact Us: e.hawkings@oxfordglobal.co.uk

Hosokawa Micron

ONE-STOP SHOP FOR TOTAL MIXING SOLUTIONS FOR PHARMACEUTICAL MANUFACTURERS Here, Bert Dekens, Application Manager at Hosokawa Micron, discusses the company’s offering for pharmaceutical powder mixing, including the Cyclomix high-shear mixer and the Nauta low-shear mixer, and how the company’s technology solutions take a broader approach to the full mixing process than simply providing a mixing machine. Hosokawa Micron has long-standing and proven experience of developing scalable powder-mixing technologies for the pharma industry, ranging from R&D to large-scale manufacturing set-ups. The company’s technology offering includes the Cyclomix, which is widely used for the high-shear mixing of cohesive dry powder inhalers (DPIs); the Conical Paddle Mixer (CPM) for mid-shear mixing; and the Nauta conical screw mixer.

CYCLOMIX – HIGH-SHEAR MIXER Blending formulations for DPIs is a delicate matter. Inhalable dry powder APIs often require lactose carriers in order to achieve the desired aerodynamic properties for delivery into the lungs, and so these two ingredients need to be carefully mixed. To disperse the fine API particles amongst the carrier, one needs to break up the cohesive forces between them, which requires a certain mechanical energy. However, if the energy applied to the formulation is too high, the adhesive forces between the carrier and the actives will also be too high, which limits separation during inhalation. Finding the right balance for the required mixing energy is a critical issue for processing DPI powders and calls for a very efficient mixer. Hosokawa Micron’s Cyclomix blending technology (Figure 1)

“Finding the right balance for the required mixing energy is a critical issue for processing DPI powders and calls for a very efficient mixer. Hosokawa Micron’s Cyclomix blending technology is a proven product on the market for high-shear blending of DPI formulations.”

Figure 1: The Cyclomix blending technology for high-shear blending of DPI formulations. 46

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Bert Dekens Application Manager T: +31 314 373 376 E: b.dekens@hmbv.hosokawa.com Hosokawa Micron BV Gildenstraat 26 7005 BL Doetinchem Netherlands www.hosokawa-micron-bv.com Copyright © 2020 Frederick Furness Publishing Ltd

is a proven product on the market for high-shear blending of DPI formulations. Cyclomix has proven to be very effective for tuning mixing energy to the delicate adhesion/cohesion balance and providing a homogenous blend without particle deterioration. Multiple systems have been sold and delivered for this challenging application. Cyclomix systems are modular and – besides offering exchangeable product bowls – can be tailored to local requirements by combining options. In order to offer the optimal product to its customers, Hosokawa Micron provides the Cyclomix in three platforms suited to the intended powder batch size, including laboratory scale (Figure 2) for 100 mL, 1 L and 2 L batches; mid-range for 5 L and 15 L batches; and large-scale able to handle batches of up to 100 L.

Hosokawa Micron

Figure 2: Mini Cyclomix lab mixer.

NAUTA – LOW-SHEAR MIXER When it comes to mixing ingredients for industrial-scale production of tablets, many pharmaceutical manufacturers opt for wet or dry granulation to minimise the risk of

segregation. Direct compression is actually a simpler and more affordable alternative to this approach. However, this approach requires manufacturers to adapt their strictly defined, validated and documented procedures. The amount of time, money and administrative effort this entails can often discourage them from switching to the direct compression method. Nevertheless, the time and cost savings made possible by the use of the Nauta mixer can make that extra effort worthwhile. Today, the tablet is the most common dosage form for medicinal products. Pharmaceutical manufacturers must adhere to high quality standards and regulations to guarantee that each tablet contains exactly the right ratio of API to excipients, such as binders, lubricants, flavourings and pigments. To achieve this, all the components must be mixed optimally before being pressed into tablet form. Many manufacturers mix the ingredients in a tumbler or container mixer and then perform either wet or dry granulation to reduce the risk of them separating again afterwards. However Hosokawa Micron’s Nauta mixer (Figure 3) offers the best of both worlds. By combining direct compression with the avoidance of segregation, it can eliminate the need for granulation, thus saving pharmaceutical manufacturers time and money. Wet and Dry Granulation In general, the risk of segregation is minimised by reducing the differences in

bulk density and particle size distribution between the APIs and excipients. To accomplish this, manufacturers often implement a granulation step to reduce this risk. Wet granulation involves multiple steps, such as granulation, drying and screening. As such, it is a time-consuming, and therefore cost-intensive, process. Alternatively, dry granulation can be used, especially when the product to be granulated is sensitive to moisture and heat. Although dry granulation is simpler, and therefore less costly than wet granulation, it often produces a higher percentage of fine granules, which can compromise the quality of the tablet. Advantages of Direct Compression A growing number of pharmaceutical manufacturers are discovering that direct compression offers a simpler, and therefore cheaper, alternative to granulation techniques. It entails the mixing of dry, freeflowing powders with a uniform particle size so that they can be directly compressed in a tablet press. The Nauta mixer is capable of eliminating the granulation step by enabling direct compression. Despite being well-known and having been first developed several decades ago, the Nauta conical screw mixer has been continuously improved in line with the very latest technological advances to keep it constantly up to date with the needs of customers in the pharma industry. It is ideal for the low-shear mixing of delicate free-

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Hosokawa Micron

flowing powders, enabling all the necessary ingredients to be blended into a completely homogeneous mixture to ensure uniform and high-precision dosages. Moreover, the Nauta is hugely flexible in terms of the filling volume, producing an excellent mixing result even if the mixer is only 10% full. This also makes it suitable for use in a multi-staged mixing process to produce low-dose tablets.

Figure 4: 3D illustration of a pharma mixing system.

TOTAL MIXING SOLUTION Hosokawa Micron, rather than simply supplying machines, also takes a broader approach to design a total mixing solution that integrates the pre- and post-processes (Figure 4). This entails a full consideration of four aspects: • • • •

How the powder is fed into the mixer What happens inside the mixing vessel How the powder is discharged How the equipment is cleaned.

For the charging and discharging of toxic materials, for instance, Hosokawa Micron can use or develop customised container docking systems, such as lift systems or split butterfly valves (Figure 5). When considering what happens inside the

Figure 5: Lift system for conical mixers. 48

vessel during the mixing process itself, it is important to take into account any ingredients the customer may need to add and how they will affect the process, including liquids, which can even be heated or cooled during mixing if necessary. Additionally, post-processing equipment can be integrated if required, such as deagglomeration equipment, sieves, cone mills, etc, to turn the mixture back into powder. In the Nauta, the conical vessel and topdriven agitation ensure that the powders will not segregate again during discharge into a tablet press, which can be a problem when container mixers are used. If desired, it can even be positioned right above a tablet press to ensure direct discharge, further contributing to maintaining the stability of the product. The fourth aspect, cleaning, is of critical importance in the pharma industry, which is why Hosokawa Micron offers complete automated cleaning in place (CIP) and sterilisation in place (SIP) installations, including the associated control systems (Figure 6). In order to eliminate

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“Hosokawa Micron, rather than simply supplying machines, also takes a broader approach to design a total mixing solution that integrates the pre- and post-processes.” the handling step and thereby reduce the risk of product contamination and increase operator safety in the case of toxic materials, the CIP and SIP skids on Hosokawa Micron machines are permanently docked. Needless to say, all the systems comply with the applicable regulations and guidelines, and come with the relevant documentation to prove it, relieving the regulatory burden on customers.

SMALL-SCALE PRACTICAL TRIALS Time is of the essence for manufacturers striving to win the race to market and secure the all-important patent for an original pharmaceutical product. In order Copyright © 2020 Frederick Furness Publishing Ltd

Hosokawa Micron

Figure 6: Cyclomix with CIP-skid. to optimally explore the cost-saving possibilities provided by switching to direct compression, it is advisable for pharmaceutical partners to contact Hosokawa Micron as early on as possible – preferably during the R&D process. After all, the formulation of each new tablet is unique, so a product-specific solution is developed together with each customer. For example, it could be beneficial for a formulation to add the excipients directly into the same mixer as the pre-mix, rather than splitting this up into individual process steps. This is precisely what the Nauta mixer facilitates. Hosokawa Micron’s test centre in the Netherlands – which, thanks to its size and wide range of capabilities, is unique in Europe – enables the company to work closely with customers to investigate such possibilities using the actual ingredients in real-life, small-scale trials. A second situation in which the direct compression approach makes sense is for generic pharmaceutical products. Generics manufacturers have to focus on reducing

“The energy required for powder mixing depends on various factors. The powder characteristics, such as the cohesion of materials and particle size, are important, of course, but other considerations include both the end-product properties and the process, safety and system requirements.” costs, even if it means they have to redesign their production process, including revalidating their procedures as necessary. The cost savings that can be achieved via direct compression without compromising on quality make it an extremely worthwhile consideration.

safety and system requirements. Due to Hosokawa Micron’s wealth of experience and in-house technology, the company is a one-stop shop for mixing systems and is able to advise each customer about the best batch mixer solution – low, mid or high shear – for their particular situation.

CONCLUSION

ABOUT THE COMPANY

The energy required for powder mixing depends on various factors. The powder characteristics, such as the cohesion of materials and particle size, are important, of course, but other considerations include both the end-product properties and the process,

Hosokawa Micron is a global supplier of process equipment and systems for the mechanical and thermal processing of dry and wet powders. The company specialises in the design and manufacture of mixing, drying and agglomeration technologies. Hosokawa Micron maintains extensive facilities for R&D, testing, manufacturing, toll processing and after-sales services, and has a total of around 170 employees. Hosokawa Micron BV is a wholly owned subsidiary of the Japanese Hosokawa Micron Corporation.

ABOUT THE AUTHOR Bert Dekens is Application Manager, Pharma, for the Hosokawa Group, focusing on DPI-blending markets. Mr Dekens holds a key position in the DPI network within the International Hosokawa Group and is well established in the DPI market.

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Company Showcase

MG2 AUTOMATION SOLUTIONS FOR INHALATION

Since 1990, MG2 has been developing automation solutions for inhalation applications, which meet the most demanding requirements of formulations on the capsule filling process. When handling powders for inhaled pharmaceutical products, there are several challenges that affect the development of the filling process. The filling process is a critical phase due to the product low dosages involved (ranging from 5 mg to 40 mg), and the weight changes. In fact, in the development of low dosage units, both the required mechanical stress to withdraw powders and then the transfer into capsules must be considered. It is necessary to identify the correct machine set-up to achieve accurate dosing without compromising the aerodynamic profile of the formulation and with it the end product’s inhalation performance. MG2 addresses and solves these issues by applying both volumetric technology in its dosator (see Figure 1) and an in-process system to control the net weight of the powder filled into each capsule.

A MODUS OPERANDI FOCUSED ON R&D AND ACADEMIC PARTNERSHIPS In addition to its technological experience, MG2’s customers can make use of the Pharma Zone, an area which totally complies with relevant pharmaceutical standards and thus offers a simulation environment particularly suitable for R&D purposes, not only for preclinical tests but also for the development of technical batches. The MG2 Pharma Zone provides an excellent level of safety for operators in all working conditions, such as either handling dangerous powders or running tests on powder behaviour under different environmental (relative humidity and temperature) conditions. 50

Figure 1: MG2 dosators incorporate volumetric technology.

“The Inhalation Consortium was conceived specifically to share knowledge and solve issues related to inhalation powders filled into capsules.” The Pharma Zone is a real trump card. It facilitates a constant dialogue between MG2 technicians and the customer. The continuous

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Company Showcase

inhalation applications, by both taking part in international research projects and establishing relationships with some of the most important operators in this field. Arising from one such partnership, the Inhalation Consortium was conceived specifically to share knowledge and solve issues related to inhalation powders filled into capsules. In addition to MG2, the consortium includes: RCPE (Graz, Austria), Meggle (Wasserberg, Germany), Qualicaps (Madrid, Spain), University of Parma’s Department of Food and Drug (Italy), and Insud Pharma (formerly Gruppo Chemo, Madrid, Spain). The Inhalation Consortium has also started a three-year research program focused on capsule behaviour during the filling phase and interaction with the physical-chemical characteristics of the powders to be dosed.

Figure 2: The Pharma Zone area facilitates a constant dialogue between MG2 technicians and the customer. a perfect environment for 360-degree trials. This pharmaceutical area (Figure 2) also serves as a strategic tool for both the research MG2 undertakes and the partnerships that it has established with many academic

institutions and pharmaceutical suppliers. For several years MG2 has adopted a scientific approach to the new challenges of the pharmaceutical market, including in particular the specific demands of

CASE HISTORIES WITH PROMINENT PLAYERS MG2 has struck up several direct co-operations with leading companies in the inhalation market.

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Company Showcase

Multinational Pharma Company Among them there is an important Italian multinational pharmaceutical company, which has chosen MG2 as its cutting-edge technology supplier. The decision results from the pharma company’s need to test new formulations that have not yet been launched onto the market, studying their behaviour during both the delicate capsule-filling stage and the weight-control phase. This co-operation took shape not only with an analytical and chemical-pharmaceutical point of view, but also under the technological profile, thus providing benefits in terms of production standard. MG2’s crossfunctional experience, strong position in the market and the presence of the Pharma Zone all benefit the collaboration. Activities carried out include: • Laboratory tests, particularly focused on machine set-up logic, with manual tests (Figure 3), which allow selection of the best dosator and the necessary adjustments to be defined in order to arrive at the required net weight.

• Short runs, made under different operation conditions, necessary to identify the best machine set-up by considering the particularly small quantities of the involved material. • Long runs, i.e. simulation of an actual batch which will be produced by the customer at a later stage. The constant co-operation between MG2 technicians and chemists from one side and the customer from the other side has made it possible to mitigate many of the usual issues faced during the development of a new formulation, by rationalising the resources in all the experimental phases in order to achieve the common goal of defining the ideal recipe. International CDMO An international CDMO with numerous European and North American sites installed an MG2 capsule filler, in a containment configuration, suitable for low-dose powders for inhalation, after having successfully assessed MG2’s technology. In this case, the customer firstly started with a FlexaLAB

model equipped with MultiNETT, the MG2 patented in-process net weight control system, then the customer continued the production stage by inserting a new high-speed capsule filler suitable for handling high-potency drugs. Thanks to the scalability of MG2 machines, the CDMO had the chance to complete its innovation path from R&D to production. These two different experiences shared a common cornerstone: MG2’s technological excellence in the inhalation drug filling process.

ABOUT THE COMPANY MG2 supplies automatic machines for the pharmaceutical, cosmetic and food industries. Machines include containment solutions, and capsule fillers for oral dosage forms and, since 1990, the company’s capsule filler offering broadened to include inhalation applications. In the late 1990s, the company entered the packaging market and now offers complete primary and secondary packaging solutions for pharma (as well as the cosmetics and food industries). MG2 was founded in 1966 by Ernesto Gamberini, who patented and introduced the first continuous-motion capsule filler on the market (Model G36). The company is based in the Italian “Packaging Valley” region. In 1987, MG2 founded a US sister company, MG America, Inc, in New Jersey, that supplies European processing, packaging, inspection and material handling equipment throughout the US, Canada and Puerto Rico.

MG2 s.r.l. Via del Savena, 18 Pianoro Bologna Italy E: marketing@mg2.it www.mg2.it/processing

Figure 3: Manual tests allow the best dosator to be selected.

IN WHICH ISSUE SHOULD YOUR COMPANY APPEAR? www.ondrugdelivery.com/participate 52

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Hovione / Copley

SEMI-AUTOMATION IN INHALER TESTING – EXPLORING THE POTENTIAL AND PRACTICALITIES In this article, João Pereira, Team Leader R&D Analytical Development, and Raquel Borda D’Água, Associated Analytical Chemist, both at Hovione, and Mark Copley, Chief Executive Officer, and Anna Sipitanou, Business Development Manager, both at Copley Scientific, discuss the semi-automation of cascade impactor testing and the benefits it can bring in terms of quality of orally inhaled product test data, and reductions in cost and effort associated with routine, critical measurements.

INTRODUCTION The automation of discrete steps of cascade impactor analysis offers opportunities to address variability in inhaler testing, while simultaneously reducing health and safety concerns and improving analyst productivity. The ability of cascade impaction to generate drug-specific aerodynamic particle size distribution data (APSD) for orally inhaled products (OIPs) is central to its utility, but necessitates systematic drug recovery from each stage of the impactor, and from the surfaces of other accessory components that complete the test set-up. This laborious task accounts for much of the manual effort associated with cascade impaction measurements and is a primary focus for automation. The rewards can be significant; however, such changes raise questions of

“A back-to-back comparative study of manual and automated drug recovery carried out by Hovione… demonstrates statistical equivalence between the methods and highlights a reduction in analyst bench time of about 40%.” Copyright © 2020 Frederick Furness Publishing Ltd

equivalence to manual methods, which must be robustly answered prior to the adoption of automated methodologies. In this article, we consider the semiautomation of cascade impactor testing focusing on those tasks, notably aspects of drug recovery that are easily tackled using off-the-shelf solutions. A back-to-back comparative study of manual and automated drug recovery carried out by Hovione, a leading contract development and manufacturing organisation, demonstrates statistical equivalence between the methods and highlights a reduction in analyst bench time of about 40%.

João Pereira Team Leader R&D Analytical Development T: +351 21 982 9000 E: jfpereira@hovione.com

THE CASCADE IMPACTION WORKFLOW

Hovione FarmaCiencia S.A. Sete Casas 2674–506 Loures Portugal

A cascade impactor is a precision instrument that fractionates a sample on the basis of particle inertia, which is a function of particle size and velocity. The workflow associated with producing drug-specific aerodynamic particle size distribution (APSD) data for an OIP can therefore be split into two discrete elements: size fractionation of the dose (by the impactor) followed by drug recovery and quantitation, to determine the drug deposition profile. The cascade impactor test set-up for any specific application is defined with reference to the device under test and the purpose of analysis, for example, whether the aim is to generate more clinically realistic data for research and product development, or

Raquel Borda D’Água Associated Analytical Chemist R&D Analytical Development T: +351 21 982 9000 E: rbagua@hovione.com

www.hovione.com Mark Copley Chief Executive Officer T: +44 1159 616229 E: m.copley@copleyscientific.co.uk Anna Sipitanou Business Development Manager T: +44 1159 616229 E: a.sipitanou@copleyscientific.co.uk Copley Scientific Ltd Colwick Quays Business Park Road No. 2 Nottingham NG4 2JY United Kingdom www.copleyscientific.com

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Hovione / Copley

“The product-specific nature of cascade impactor test set-ups and the complexity of the measurement process directly influence the feasibility of end-to-end automation, which is rarely, if ever, cost effective. Conversely, automating specific steps with off-the-shelf solutions can be highly beneficial.” to confirm batch-to-batch consistency for product release. A detailed discussion of cascade impactor test set-up and the issues associated with method development lies beyond the scope of this article, but is well covered by Bonam et al (2008).1 Once a test set-up has been established, routine analysis is initiated by actuating the device to release a dose into the impactor. A vacuum pump draws the sample-laden air through the stages of the impactor at a constant, defined volumetric flow rate, causing the deposition of particles above a certain cut-off diameter on the collection surface of each stage; each subsequent stage captures progressively smaller particles. Multiple actuations are frequently required to ensure a quantifiable amount of drug on each collection surface and to guarantee method repeatability. At the end of this first part of the analysis, multiple doses of the drug product are distributed, depending on the exact test set-up, across: the mouthpiece adaptor (MA), the induction port (IP) – the interface between the device and the impactor – the pre-separator (PS) when used, each stage of the impactor, and the micro-orifice collector (MOC) or final filter. Completion of the analysis involves the rigorous recovery of samples from each of these surfaces. This involves wetting and rinsing each surface to dissolve the deposited sample with a suitable solvent and produce solutions of an adequate concentration for assay, typically via liquid chromatography (LC). The resulting data are converted into APSD metrics specifically for the API, typically using dedicated software. The product-specific nature of cascade impactor test set-ups and the complexity of the measurement process directly influence the feasibility of end-to-end automation, which is rarely, if ever, cost effective. Conversely, automating specific steps with off-the-shelf solutions can be highly beneficial. The cost of such solutions is far more accessible than a bespoke automation project and they can deliver significant 54

improvements in day-to-day practice, reducing analyst fatigue and stress, and the risk of repetitive strain injury (RSI) by eliminating time-consuming repetitive tasks. Critically, automation can improve data quality, accuracy and integrity by eliminating the effect of operator-tooperator variability and handling errors. For many organisations, the number of samples lost due to simple but impactful handling errors is significant and results in, at best, repeat analyses and, at worst, a costly, time-consuming investigation. For example, automated shake-andfire systems ensure highly repeatable device actuation in metered dose inhaler (MDI) testing by applying a consistent, well-defined device use regime (between actuations), shaking protocol and actuation force profile. This can help to significantly reduce variability in the delivered dose and, by extension, the whole measurement.2 More generally, for all OIPs it is the process of drug recovery that is most amenable to automation, with off-the-shelf solutions ranging from simple rinsing devices through to sophisticated systems for complete automation.

FOCUSING ON DRUG RECOVERY Developing a robust, optimised method for drug recovery involves the careful consideration of issues such as: • Which solvent is most appropriate – while highly volatile solvents may be essential to achieve complete dissolution, solvent evaporation can compromise pipetting and the delivery of accurate solvent volumes. Furthermore, volatility enhances the risk of sample concentration due to solvent loss during storage or the drug recovery process. • How much solvent should be used – high solvent volumes ease complete drug dissolution by improving sink conditions, but simultaneously reduce drug concentration, potentially

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compromising the accuracy of the assay. Wide variation in the amount of drug that deposits on any given stage of the impactor can make it difficult to ensure complete dissolution of the drug at high loadings while simultaneously ensuring that the sample has a concentration above the limit of detection (LOD)/ limit of quantification (LOQ) for stages on which drug deposition is minimal. This issue can be especially challenging for products with more than one active ingredient. There is also a positive environmental impact in lowering solvent content for extraction purposes. • The best method to promote rapid and effective drug dissolution – to ensure complete dissolution, the drug and solvent must be in contact for an adequate length of time. Agitation accelerates dissolution and helps to ensure complete surface wetting; the application of ultrasonics is an option for less easily dissolved actives. • What equipment to use to minimise sample degradation – any container in which recovered drug solutions are going to be held, including vials used for analysis, requires careful consideration to avoid, for example, sample loss to vial walls, absorption of the active from the solution and/or solvent evaporation. A validated drug recovery method may be entirely manual but, where this is the case, analysis will necessarily involve a number of repetitive activities that are either significantly prone to error or physically arduous, or indeed both. Prime examples include pipetting and agitation of a specific test component with a defined aliquot of solvent. With these tasks, even simple devices, such as automated pipettes or rocking/rinsing devices, can make a major difference. For example, the Sample Preparation Unit Model SPU 2000 automates internal rinsing of the USP/PhEur induction port and the Next Generation Impactor (NGI) pre-separator, delivering consistent wetting of the internal surfaces and reproducible dissolution via the application of a defined agitation pattern for a set period of time. Semi-automation with simple devices of this type is typically low cost and low risk, and the economic payback can be attractive, with analysts freed for higher value activities. On the other hand, more sophisticated off-the-shelf solutions, such as the NGI Assistant, can prove an even more beneficial investment over the long Copyright © 2020 Frederick Furness Publishing Ltd

Hovione / Copley

Manual recovery

Automated recovery 3x

Manual shaking

Gentle agitation (of NGI cups)

Automated shaking

1 run: ~75 mins 3 runs: ~225 mins

Automated drug recovery (of NGI cups)

1 run: ~50 mins 3 runs: ~140 mins

Figure 1: Copley Scientific equipment was used in many of the manual and automated drug recovery workflows in the study. term. Systems which automate multiple steps of the drug recovery process may be associated with higher capital expenditure but can deliver more substantial gains by simultaneously addressing multiple sources of measurement variability. The NGI Assistant automates drug recovery from the point of solvent dispensation and drug dissolution through to the presentation of sample solutions in industry-standard vials, ready for liquid chromatography (LC) analysis, thereby eliminating any requirement for manual pipetting, agitation or LC sample preparation. In the following study, predominantly manual analysis was compared with more fully automated analysis using this system to demonstrate a) the time savings are accessible and b) whether the data generated are strictly equivalent.

CASE STUDY: COMPARING MANUAL AND SEMI-AUTOMATED DRUG RECOVERY FOR CASCADE IMPACTOR TESTING OF A DPI APSD data for a TwinCaps® single-use dry powder inhaler (DPI) were generated using two different methods for drug recovery (Figure 1): an essentially manual recovery method aided by an automated solution for agitation of the solvent in the NGI collection cup tray Copyright © 2020 Frederick Furness Publishing Ltd

(NGI Gentle Rocker) and a fully automated recovery with an NGI Assistant. Testing was carried out using an in-house method developed in accordance with the relevant general chapter of the PhEur.3 An NGI with USP/PhEur induction port and pre-separator was used with a test flow rate of 38 L/min, determined on the basis of a 4 kPa pressure drop across the device. A mixed solvent was used for drug recovery (details not specified) and the resulting solutions were quantified using an HPLC system (MA, US). HPLC was carried out using a silica-based column with a mixed aqueous and organic mobile phase (flow rate 0.8 mL/min) and an injection volume of 100 µL. HPLC data were analysed using Empower 3 software (MA, US). CITDAS software (Version 3.10) was then used to generate APSD metrics for the inhaler including fine particle dose (FPD), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). A total of 23 replicate tests were carried out in total, 10 by Analyst One using the manual drug recovery method, three by Analyst Two using the same method, and 10 using the more automated method. Mass balances checking (referencing a label claim of 135 µg) confirmed that all runs fulfilled the relevant mass balance criteria: emitted dose (ED) lying between 75% and

125% of label claim.3 Equivalency between the datasets was assessed via t-testing, a statistical method for determining the extent to which two datasets are identical. Table 1 shows the percentage variance in the amount of drug recovered from each stage of the impactor for the runs carried out by Analyst One alone and for the two analysts combined. These data illustrate how, in general, variability increases when measurements are carried out by multiple analysts. This intuitive

Analyst 1

Analyst 1 and 2

Stage 1

10%

Stage 2

14%

Stage 3

Stage 4

Stage 5

Stage 6

Stage 7

MOC

Table 1: Percentage variability in the mass (µg) recovered from each stage of the impactor by Analyst 1, and by Analyst 1 and 2 combined.

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Hovione / Copley

p-value

t-Stat

t-Critical

Stage 1

0.28

-1.12

2.10

Stage 2

0.38

-0.89

2.08

Stage 3

0.61

-0.51

2.08

Stage 4

0.36

0.94

2.11

Stage 5

0.33

1.00

2.12

Stage 6

0.28

1.12

2.14

Stage 7

0.73

-0.35

2.10

MOC

0.19

-1.36

2.12

Table 2: Comparing the equivalence of manual and automated drug recovery.

p-value

t-Stat

t-Critical

FPD

0.46

0.76

2.10

MMAD

0.39

-0.88

2.09

GSD

0.21

-1.31

2.09

Table 3: Critical metrics generated using manual and automated drug recovery methods were shown to be statistically equivalent. finding stems from the fact that manual analyses are inherently subject to both intra- and inter-operator variability; where more than two operators are responsible for analysis, variance might reasonably be expected to be even higher. Furthermore, the impact of operator variability is likely to be higher with a completely manual method, in the absence of the automated solution for solvent agitation. Since it would be rare for analysis for a given product always to be carried out by a single analyst, the combined Analyst One and Two dataset was selected as the more realistic basis for comparison of the impact of switching to automated drug recovery. Table 2 shows t-test data (two-sample, unequal variances) for a comparison of the results produced by the established, more manual method (Analyst One and Two) and via automated drug recovery.

When automating a manual method, it is crucial to confirm that the results are equivalent using statistical methods such as these. In the absence of such crossvalidation, systematic differences can be introduced that ultimately result in the product failing to meet specification. Here, analysis shows that, for every stage, the absolute value of the t-statistic lies below t-critical and the associated p-value is well above the threshold value of 0.05, confirming statistical equivalence. Robust equivalence is also observed in the APSD parameters generated by each method (Table 3). Monitoring analyst bench time during the study enabled calculation of the productivity gains accessible by switching to the more automated method. The results indicate that analyst bench time is reduced by around 40%, a substantial increase in productivity. The study also provides a good

“The semi-automation of cascade impaction has an important role to play in improving the quality of OIP test data, while at the same time reducing the cost and effort associated with routine, critical measurements.” 56

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illustration of the potential to progressively adopt automation solutions, with crossvalidation at each stage reducing the risk of introducing systematic differences.

CONCLUSION The semi-automation of cascade impaction has an important role to play in improving the quality of OIP test data, while at the same time reducing the cost and effort associated with routine, critical measurements. This study illustrates how sophisticated, easy-to-use, off-the-shelf solutions can be used to generate statistically equivalent data and deliver major productivity gains, reducing analyst bench time by around 40%. By freeing analyst time for more valuable, less repetitive tasks, such solutions can help to minimise the risk of out-ofspecification results, address health and safety concerns, and, at the same time, deliver an attractive return on investment.

ABOUT THE COMPANIES Hovione is a specialised, fully integrated CDMO able to support drug substance, drug product intermediate and drug product at the same production site. With an exceptional regulatory track record, including the FDA, and 60 years of experience, the company offers a broad range of process and drug product development services. From small molecule API manufacturing to formulated drug product delivery, Hovione seamlessly integrates all drug product development phases, from small-scale feasibility studies to commercial-stage production. Hovione has focused resources into continuously developing expertise in particle design and formulation development for highly sophisticated inhalation APIs. From API to crystal, particle to powder blend, capsule to inhaler – the company masters every development step. Hovione also offers a full range of simple, patented, cost-effective DPIs (disposable, capsule, blister and large dose DPIs). Copley Scientific is recognised as a leading manufacturer of inhaled drug test equipment. Products include delivered dose sampling apparatus, Andersen and Next Generation Impactors, critical flow controllers, pumps, flow meters and inhaler testing data analysis software. Copley Scientific also supplies novel systems for improving productivity and Copyright © 2020 Frederick Furness Publishing Ltd

Hovione / Copley

IVIVCs, including semi-automation, abbreviated impactors, breath simulators and the Alberta Idealised Throats. Training, calibration, maintenance and impactor stage mensuration services are also available. Founded in 1946 in Nottingham, UK, Copley Scientific remains family owned and managed. The company continues to work closely with industry groups and leading experts to bring relevant new products

to market, with all equipment backed by expert training and lifetime support.

REFERENCES 1. Bonam M et al, “Minimizing Variability of Cascade Impaction Measurements in Inhalers and Nebulizers”. AAPS Pharm Sci Tech, 2008, Vol 9(2), pp404–413.

2. Copley M et al, “Optimizing the role of automation in variability reduction strategies for delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD) testing of inhaled drug products”. Inhalation, Dec 2019. 3. “Aerodynamic Assessment of Fine Particles”. European Pharmacopoeia, Chapter 2.9.18.

ABOUT THE AUTHORS João Pereira joined Hovione in 2015 as part of the R&D Drug Product Development – Analytical Development group, where he worked on analytical method development for new drug products and drug product intermediates. In 2017, Mr Pereira became lead analytical chemist supporting several development programmes of drug product and intermediate drug product. In 2019, he became team leader in Analytical Development, where analytical method development in the fields of physical and performance characterisation are performed. Mr Pereira holds an MSc in Pharmaceutical Sciences from the Faculdade de Farmácia da Universidade de Lisboa (FFUL). He has previously worked in the pharmaceutical chemistry field in the Research Institute for Medicines (iMed.ULisboa) and in a quality control unit in Laboratórios Vitória. Raque Borda D’Água joined Hovione in 2018 as part of the R&D Drug Product Development – Analytical Development group, where she worked on analytical method development for new drug products and drug product intermediates. In 2019, Ms Borda D’Água became an analytical chemist in Hovione R&D Analytical Development, focusing on performance and physical characterisation methodologies to support several development programmes. Prior to Hovione, Ms Borda D’Água worked as a Research fellow at Cenimat|i3N in Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa (FCT-UNL), integrated into several projects focused on the design and build of microfluidic systems and materials characterisation. Ms Borda D’Água holds a BSc and a MSc in Biochemistry from FCT-UNL. Her Master’s thesis focused on impregnation development techniques of low-cost zinc oxide nanoparticles with antibacterial properties in fabrics performed in Cenimat|i3N in collaboration with the Department of Science and Technology of Biomass. Mark Copley graduated from the University of Bath, UK, in 2000 with a Masters Degree in Aerospace Engineering. For eight years he was Technical Sales Manager and product specialist for Copley Scientific’s range of inhaler testing equipment, before becoming the Sales Director in 2009. Mr Copley is now Chief Executive Officer for the company. Mr Copley is considered a leading authority in testing methods and systems for MDIs, DPIs, nebulisers and nasal sprays; authoring and contributing to more than 50 published articles. He also provides application support and consultancy, runs focused training workshops for the inhaled drug testing sector of the pharmaceutical industry and sits on the editorial advisory panel of Inhalation Magazine. An invited member of the European Pharmaceutical Aerosol Group impactor sub-team, Mr Copley has also made recommendations to the Inhalanda working group, leading to subsequent revisions to PhEur and USP monographs. As part of Copley Scientific's associate membership of the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS), Mr Copley participates in a number of working groups with a view to enhancing the regulatory science of orally inhaled and nasal drug products (OINDP). Anna Sipitanou holds a BSc in Chemistry and an MSc in Drug Discovery & Pharmaceutical Sciences. Having joined Copley Scientific in 2017, Ms Sipitanou plays a key role in the company’s technical and sales support services, including the training of customers on a wide range of pharmaceutical testing equipment, with a particular focus on OINPD testing. Having worked closely with pharmaceutical companies on a wide range of OINDP projects, Ms Sipitanou has gained specialist knowledge of the regulatory requirements for both delivered dose uniformity and aerodynamic particle size distribution testing, as well as extensive experience in methods to improve in vitro-in vivo correlations (IVIVC) and other specialist testing applications, including generic drug development, inhaled dissolution and facemask testing.

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Upperton

PULMOCRAFT ™: ENGINEERING SPRAY DRIED POWDERS FOR PULMONARY DELIVERY Here, Richard Johnson, PhD, Founder and Chief Executive Officer, Upperton Pharma Solutions, discusses the techniques of jet milling and spray drying for the production of formulations for dry powder inhalers, and introduces Upperton Pharma’s PulmoCraft™ technology, which combines the advantages of both. Pulmonary delivery is widely established as a viable dosage form for treating local airway diseases, with additional potential for systemic drug delivery. Within this space there are a number of possible delivery approaches that can be undertaken. These include formulations for dry powder inhalers (DPIs) and pressurised metered dose inhalers (pMDIs). Each of these delivery options has its own benefits and limitations and, as such, the applications they target differ. However, if the target patient profile allows, companies typically look towards using DPIs for their finished product. When developing a DPI formulation, particle engineering is a major factor in a successful development programme. Indeed, the aerosolisation of the powder is key to delivery of the therapeutic. Key factors in the successful delivery of drugs from a DPI are the formulation’s particle size and aerodynamic performance. In short, the particles being inhaled need to have the correct aerodynamic properties to exit the device on inhalation and then deposit in the correct region of the lung. If the alveolar region (or “deep lung”) is being targeted, an aerodynamic particle size in the 1–5 µm range is usually required. Two approaches have been widely used to create suitable powders for lung delivery: jet milling and spray drying. Both techniques have been used to make particles in the 1–5 µm size range. In this article, 58

we will compare and contrast the advantages and limitations of each of these traditional techniques, before focusing on a relatively new approach named PulmoCraft™ (Figure 1), which has successfully combined the flexible formulation technology of spray drying with the precision engineering of jet milling to produce large quantities of powder suitable for delivery in commercially available DPIs.

MANUFACTURING POWDERS USING JET MILLING OR SPRAY DRYING Particles suitable for lung delivery require an aerodynamic size between 1-5 µm in order to deposit in the alveolar regions; the portion of particles in a DPI formulation that meets this criterion is often referred to as the respirable fraction. The most widely used technology for creating these particles is jet milling.

“In recent years, there has been growing interest in using spray drying to create microparticles that can deliver drugs into the lung without the need of a larger carrier particle.”

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Dr Richard Johnson Founder and Chief Executive Officer T: +44 115 855 7050 E: rjohnson@upperton.com Upperton Pharma Solutions Albert Einstein Centre Nottingham Science Park Nottingham NG7 2TN United Kingdom www.upperton.com Copyright © 2020 Frederick Furness Publishing Ltd

Upperton

powders for DPIs, there are some classes of API that are not suitable for this process, for example: • Waxy or “sticky” APIs that do not fracture on collision in the grinding chamber but instead aggregate together • Sensitive APIs that cannot withstand the high shear forces created during the jet milling process • Unstable APIs (e.g. peptides, biologics) that require other excipients to be mixed with them at a molecular level to impart the necessary stability on storage in the dry state.

Figure 1: Overview of the PulmoCraft™ manufacturing process. Jet-milled particles are notoriously cohesive in nature, due to their high surface to volume ratio. The resultant electrostatic, Van der Waals and capillary forces result in powders that have poor flow characteristics and are difficult to disperse. To overcome this inherent problem, some formulations contain larger “carrier” excipients, such as lactose or mannitol, that loosely bind the smaller drug particles before releasing them on delivery. In recent years, there has been growing interest in using spray drying to create microparticles that can deliver drugs into the lung without the need of a larger carrier particle. These spray-dried microparticles typically consist of an excipient (e.g. mannitol) and an API, in the form of a spray-dried dispersion, which can be amorphous or crystalline in nature. Micronisation: Production of Respirable Particles by Jet Milling The most common pharmaceutical jet mill used for micronisation (the manufacture of fine particles) is the spiral jet mill or “pancake mill”. Using this technique, larger Copyright © 2020 Frederick Furness Publishing Ltd

drug particles are fed into the grinding chamber and immediately accelerated by the high gas flow (typically in the range of 4–8 barg). The particles are reduced in size by collision with each other and the walls of the grinding chamber. By adjusting the milling air pressure and the powder feed rate it is possible to create particles of the required size range required for lung delivery. For the small particles sizes required to be in the respirable range, it may require several passes through the jet mill before the target particle size can be achieved. Production of Respirable Particles by Spray Drying Whilst jet milling is a highly efficient and widely used technique for producing

For these more sensitive or difficult to formulate molecules, spray drying offers an alternative route for engineering particles of the correct aerodynamic size range needed for deep lung delivery. Spray drying involves making a solution that contains both the API and the excipients required to formulate and stabilise the molecule. This solution is then pumped into the spray dryer and atomised into small droplets as the feed solution enters the drying chamber. Almost immediately on entry into the drying chamber, the fine droplets evaporate (usually in milliseconds) to create dry powder particles. These particles are carried on the drying gas flow and separated from the subsequent exhaust gas by a cyclone collection system. By adjusting the spray-drying conditions it is possible to “engineer” the particle size produced by the spray-drying process. There are several processing conditions that have to be set and monitored during the process as they have a significant impact on particle size of the powders produced. The Challenge of Producing Respirable Spray-Dried Particles at Commercial Scales Producing particles in the respirable size range is relatively straightforward on small lab-scale spray dryers such as a Büchi B-290 (Büchi Labortechnik, Flawil, Switzerland) and ProCepT 4M8-TriX (ProCepT, Zelzate, Belgium). These dryers are used routinely on an experimental basis

“A serious challenge soon becomes apparent when practitioners begin the process of scaling up their spraydrying processes following successful early stage trials.” www.ondrugdelivery.com

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for producing small quantities of powder (in the gram scale) and are designed to produce and subsequently collect small particles (in the 1–5 µm size range). A serious challenge soon becomes apparent when practitioners begin the process of scaling up their spray-drying processes following successful early stage trials. These larger spray dryers, such as those produced by GEA Niro (Søborg, Denmark), are routinely fitted with spray nozzles and cyclones designed to produce (and collect) particles of a much larger size. For example, a GEA Niro PSD-1 (Figure 2) will typically produce and collect particles with a mean size in the 10–15 µm range and recovery of particles below 5 µm will be much more problematic with associated low yields. Scaling up to the larger PSD-3 or PSD-5 commercial scale spray dryers provides even greater challenges. These dryers are designed to create even larger particles, with mean sizes typically in the 10–100 µm size range. The spray nozzles and the associated cyclones provided as standard are not capable of producing and subsequently collecting the small particles required for pulmonary delivery. The challenge of particle collection can be overcome to an extent by engineering higher efficiency cyclones that can more efficiently collect these small particles (or using several cyclones in series). However, even then, solutions with low solid contents have to be spray dried in order to yield the small particles needed, which pushes up production costs whilst process yields suffer as a result. In conclusion, the ability to spray dry large quantities of particles in the respirable range remains a major challenge when looking to scale up a process that was initially successfully developed on a laboratory scale spray dryer.

PULMOCRAFT™: COMBINING THE BENEFITS OF SPRAY DRYING AND JET MILLING The PulmoCraft™ technology, developed by Upperton Pharma Solutions, has combined two established pharmaceutical manufacturing processes, spray drying and jet milling, to create a process capable of producing large quantities of spray-dried powder with particle sizes in the respirable size range at scale, with lower costs and better yields than can be produced by spray drying alone. 60

Figure 2: A GEA Niro PSD-1 spray dryer. VMD* (µm)

X10 (µm)

X50 (µm)

X90 (µm)

Spray dried on B-290 spray dryer

2.03

0.71

1.74

3.76

Spray dried on Niro Mobile Minor

22.97

4.16

17.86

51.43

Particles produced by PulmoCraft™ technology**

2.43

0.77

2.00

4.55

Processing conditions

*Volume Mean Diameter **Spray-dried powder produced on Mobile Minor and further processed by jet milling

Table 1: Particle size distribution of the spray-dried and PulmoCraft™ powders by laser diffraction. Case Study: Production of Respirable Powders Using the PulmoCraft™ Technology As an example of the flexibility and utility of the PulmoCraft™ technology, batches of particles containing mannitol as an excipient and caffeine as an API were manufactured. The aim was to produce powders suitable for respiratory delivery using two approaches: • Conventional spray drying: Spray drying on a Büchi B-290 laboratory spray dryer using the processing conditions required to produce small particles suitable for respiratory delivery: 2% w/w liquid feed concentration, 5 barg atomisation pressure, 2 g/min liquid feed rate.

• PulmoCraft™ technology: Spray drying on a larger Mobile Minor spray dryer (GEA Niro) using processing conditions required to produce larger particles; 10% w/w liquid feed concentration, 1 barg atomisation pressure, 20 g/min liquid feed rate. Spray-dried powder recovered and further processed on jet mill to produce particles in respirable size range. The spray-dried powders were collected and sized by laser diffraction. The size distribution of the spray dried particles produced on the two spray dryers is shown in Table 1.

“The PulmoCraft™ technology is capable of producing particles of the desired size range targeted for pulmonary delivery. Indeed, the particle sizes achieved were comparable with those from the B-290 research spray dryer, despite being produced on a much larger Mobile Minor spray dryer that routinely creates much larger particles...”

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Based on the particle sizes of the spraydried powders produced, the small batch of particles produced on the Büchi B-290 were of the desired size range for pulmonary delivery. However, the particles produced on the larger Mobile Minor spray dryer were significantly larger than those required for efficient delivery into the deep lung. In a further processing step, the larger particle size of the spray-dried powder produced on the Mobile Minor was further modified using jet milling to achieve the target 1–5 µm particle size range (PulmoCraft™ technology). The sizes achieved before and after jet milling are also shown in Table 1. This demonstrates that the PulmoCraft™ technology is capable of producing particles of the desired size range targeted for pulmonary delivery. Indeed, the particle sizes achieved were comparable with those from the B-290 research spray dryer, despite being produced on a much larger Mobile Minor spray dryer that routinely creates much larger particles, but has a significantly higher processing capacity when operated under fairly standard processing conditions. Further analysis was undertaken to confirm that the PulmoCraft™ particles had suitable aerodynamic properties, comparable with the smoother, more-spherical spraydried powders of the same size range. The aerodynamic particle size diameters of both batches were measured by inertial impaction using an Andersen cascade impactor (ACI) at a flow rate of 60 L/min. Formulations were filled into size 3 hypromellose capsules and delivered from Plastiape HR RS01 devices (Plastiape, Osnago, Italy). Two doses (capsules) containing 35 mg fill weight were administered per ACI test.

Process

Fine Particle Fraction (%)

MMAD* (µm)

Spray Drying

63.0

3.3

PulmoCraft™

63.0

3.3

*Mass Median Aerodynamic Diameter

Table 2: Aerodynamic particle Size Distribution by ACI. The results obtained are summarised in Table 2 and show that the aerodynamic performance of the spray-dried and the PulmoCraft™ particles, delivered from the Plastiape device, were effectively identical to the Büchi B-290 spray-dried particles in this particular study.

produce batches of respirable powders that have excellent aerodynamic performance with the potential for commercial scale manufacture, without significant changes to conventional spray drying equipment.

CONCLUSION

Upperton Pharma Solutions is a specialist CDMO, offering clients a complete development package: early feasibility studies, process optimisation, scale up and clinical trial (GMP) manufacturing. The company has experience working with a range of dosage forms and the expertise to develop challenging molecules. Upperton’s formulation work is complemented by a comprehensive range of analytical services. The company’s core expertise is in spraydrying technology, which has an everexpanding list of applications. Upperton has an extensive, multinational client-base, ranging from small start-ups to global pharma companies and the company prides itself on its client-focus, flexible approach and scientific excellence.

Whilst jet milling remains the most widely used technique for producing powders in the respirable size range, the use of spray drying to produce powders suitable for delivery by a DPI is of growing interest. This interest is driven by a requirement to formulate ever more difficult-to-handle APIs, including new biologics. Whilst early-stage studies are delivering promising results, there remains a significant challenge when scaling up spray-drying processes from small lab-scale dryers to the larger spray dryers needed to produce commercial batches on a multi-kilogram scale. These challenges include both making particles small enough to be respirable as well as collecting them after they have been produced in the dryer. An alternative approach is to combine traditional spray drying processes with the particle engineering capabilities of jet milling. This new approach, known as PulmoCraft™, has been successfully used to

ABOUT THE AUTHOR Richard Johnson founded Upperton Pharma Solutions in August 1999, and continues to play a key role in the management and strategic development of the company. With over 30 years of experience in the pharmaceutical, biotechnology and drug delivery fields, Dr Johnson previously held senior management positions at Andaris Limited (Vectura) and Delta Biotechnology (now Albumedix, Nottingham, UK). Dr Johnson holds an honours degree in Biology from University of York (UK) and a PhD from the University of Warwick (UK) and has a proven track record in successfully developing innovative pharmaceutical products from early feasibility studies through to commercial products.

ABOUT THE COMPANY

BIBLIOGRAPHY • Marianecci C et al, “Pulmonary Delivery: Innovative Approaches and Perspectives”. J Biomat Nanobiotechnol, 2011, Vol 2(5), pp 567–575. • De Boer AH et al, “Dry powder inhalation: past, present and future”. Expert Opin Drug Deliv, 2017, Vol 14(4), pp 499–512. • Louey MD, Van Oort M, Hickey AJ, “Aerosol Dispersion of Respirable Particles in Narrow Size Distributions Produced by Jet-Milling and Spray-Drying Techniques”. Pharm Res, 2004, Vol 21(7), pp 1200–1206.

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ECONOMIC OPERATORS UNDER THE EU MDR: THE NEW REQUIREMENTS In this article, Beth Crandall, Managing Director, Global Solutions Delivery Leader at Maetrics, spells out the new requirements for economic operators under the EU Medical Device Regulation. There is still a lot of confusion surrounding the EU Medical “Pharma companies will need to Device Regulation (MDR) and undergo much stricter oversight for its implications for life sciences companies – notably regarding the ancillary device component of economic operator (EO) their combination products and will requirements. The delay of the therefore need to verify compliance EU MDR deadline to May 26, 2021 is therefore a welcome throughout their supply chain.” development for the industry. This additional time will allow businesses to better prepare for the complex changes in regulation and in Europe, additional industry sectors thoroughly address the specific requirements will be impacted. One of the significant that relate to their EOs. changes to the regulation – affecting any In addition to medical device businesses, company with products that now qualify pharmaceutical, biopharma and biologics as medical devices – is the new concept of companies should also be informed of the EOs. When the new EU MDR comes into implications of the EU MDR for any of effect, the responsibilities and requirements their products that meet the definition of a will extend to not only manufacturers but medical device. Under the regulation, pharma also importers, distributors and authorised companies will need to undergo much representatives. Under the EU MDR, EOs stricter oversight for the ancillary device share the duty of ensuring compliance. Issues component of their combination products from any one of the EO entities can have and will therefore need to verify compliance direct legal and compliance implications for throughout their supply chain and confirm the other EOs in the supply chain (Figure 1). that all EOs are fulfilling their responsibilities. The manufacturer, importers and In this article, we help to break down these authorised representatives must also prepare new responsibilities into digestible parts with to be registered. Given the delayed launch the aim of responding to some of the queries of the European Database on Medical and concerns in the industry. Devices (EUDAMED), this process of Previously, compliance for medical registration is still uncertain. It will be devices was a topic that mostly concerned important to stay up to date as new guidance device manufacturers. However, due to the is provided, as an alternative method of changes to the rules defining medical devices registration may be provided.

Beth Crandall Managing Director, Global Solutions Delivery Leader T: +01 877 623 8742 E: information@maetrics.com Maetrics Blenheim Court Huntingdon St Nottingham NG1 3BY United Kingdom

Figure 1: The economic operators affected by the EU Medical Device Regulation. 62

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DISTRIBUTORS

“Manufacturers will continue to play a pivotal role in ensuring compliance with their specific requirements, as well as with the requirements of their EOs across the supply chain.”

MANUFACTURERS Even as regulatory responsibility is being increasingly shared, manufacturers must still ensure compliance with the applicable regulations if they wish to continue placing their devices on the EU market. Manufacturers will continue to play a pivotal role in ensuring compliance with their specific requirements, as well as with the requirements of their EOs across the supply chain. Manufacturers should map out their supply chain and identify each EO entity as defined in Article 2 of the EU MDR. This important mapping will serve as a foundation for the overall efforts to assess and confirm the ability of their EOs to fulfil their responsibilities. Manufacturers should also confirm the right personnel are ready to manage EOs through supplier controls and audits. There are many other new requirements for manufacturers which apply at different times, depending on the class of device and the CE mark expiration date for current devices on the market. Some requirements apply on the date of application, May 26, 2021, such as the requirement to register and comply with post-market surveillance requirements. Other new requirements will not be implemented until much later,

including the requirement for having unique device identification (UDI) on the products, which will be implemented, based on the risk class of the device, from May 2025.

IMPORTERS According to Article 2 of the EU MDR, importers are those entities which place devices from a third country on the EU market. Importers will see a significant change to their expectations and requirements. They must now meet specific regulatory requirements and verify information from the manufacturer. For example, they will have obligations relating to non-conforming products, product recalls and vigilance incidents. This means that, should importers identify a non-conforming device, they must have a system in place to notify the manufacturer, the authorised representative and the competent authority. Other responsibilities include keeping a copy of the Declaration of Conformity of the device and copies of any certificates, amendments and supplements. They must also provide full co-operation to provide samples of the device and access to it. These duties are new to most importers and may require additional resources with specific expertise to be successfully implemented.

Distributors, just like importers, previously had no responsibilities under the European Medical Device Directive (MDD). After the date of application, they will be attributed a more active role in ensuring the compliance of the products that they distribute. Although they are the only EO entity not specifically listed as being jointly and severally liable, they will be required to act with due care and ensure that storage or transport conditions comply with those set out by the manufacturer. They must also verify that instructions for use (IFUs) are included with each device (where required) and must ensure that the CE mark, Declaration of Conformity and any required unique device identification (UDI) is present. They must also report incidents to manufacturers within their distributor agreements.

AUTHORISED REPRESENTATIVES Where the manufacturer of a device is not established in a member state, the device may only be placed on the EU market if the manufacturer designates an authorised representative. Entities falling under this category must register themselves in EUDAMED – or whichever alternative EO registration system is adopted until EUDAMED is implemented. Authorised representatives must also have access to a person responsible for regulatory compliance (PRRC). After the date of application, authorised representatives will also need to allow for financial coverage with respect to any potential “liability”, as they will be made

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jointly liable for devices, alongside the importer and manufacturer. These new requirements and increased legal liability present new challenges for the role of authorised representatives, and may require organisational authority changes for certain businesses.

CONCLUSION With so many new responsibilities spread across the EOs in the supply chain (Figure 2), manufacturers will do well to engage their regulatory teams and educate executive management about the implications of these changes. Involving the executive management of the company will help during assessments of legal impact, product portfolio decisions and resource implications, including decision-making authority and staffing

levels. All EO entities alike should begin tackling these requirements now, in order to have all their systems and processes correctly set up before the EU MDR deadline. The consequences of non-compliance – which may involve losing market access and facing new legal liability – must be carefully considered by executive management. Given the complexity of these changes, this is an ideal time for businesses to reach out to external experts for guidance, and to assess and confirm compliance across their EO network.

pharmaceutical and biotechnology companies. With offices throughout Europe and North America, Maetrics can assist with local, regional or global compliance needs. Maetrics is part of R&Q Holdings LLC.

ABOUT THE AUTHOR Beth Crandall is a respected leader who brings more than 15 years of experience in the life sciences industry, specialising in the regulated medical device market. She also has a strong background of leading large quality system programmes and implementing changes to related policies, procedures and systems. Ms Crandall uses organisational change techniques to maximise productivity, while achieving business and compliance objectives. She has a Bachelor of Arts degree from the College of St Thomas (Saint Paul, MI, US) in business administration, human resource management.

ABOUT THE COMPANY Founded in 1984, Maetrics is a global lifesciences consulting firm focused exclusively on regulatory, quality and compliance solutions for medical device, diagnostic,

“All EO entities alike should begin tackling these requirements now, in order to have all their systems and processes correctly set up before the EU MDR deadline.”

Inhalation & Respiratory Drug Delivery US: In-Person 29 - 30 June 2021 | San Diego, USA Leading experts will discuss the latest challenges and innovations in inhaled therapy formulation and device development, with case studies on alternative therapeutic areas and in-depth presentations on pioneering advancements in inhaled biologics and COVID-19. This event will examine the latest developments in inhaled vaccines and antibiotics, as well as challenges and trends in respiratory device-mediated delivery.

Agenda at a Glance DAY ONE - 20 April 2021

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Formal and informal meeting opportunities oﬀer delegates the chance to discuss key solutions with leading service providers:

• Inhalation Drug Delivery

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