DPI development: Understanding the technical challenges
As first AppeAred in inhalation June 2012DPI development: Understanding thetechnical challengesDPIs are challenging to design new DPI remains a rare event, and the success rate of a typical DPI development currently stands at around 10and should not be viewed percent. So why is DPI development so difficult?merely as “packaging.” Varied and diverse challenges When approaching a DPI development program, R&DDavid Harris and Andrew Pocock teams often appear to be surprised by the wide andTeam Consulting diverse range of technical challenges involved. Efficient internal communication between the groups responsible for formulation development, device design, regulatory affairs, marketing and commercialization is absolutelyThe first commercially-successful dry powder inhaler essential. Without it, there is a danger of silo mentality,(DPI), which entered the market more than 40 years ago, with each group believing they have sole responsibilitywas developed by Dr. Roger Altounyan, a former Spitfire for the success of the product. In reality, all aspectspilot, medical doctor and asthma sufferer, who was must be satisfied; they are equally important. The deviceinspired by the propeller on his fighter plane to develop is the interface between the user and the drug. The waythe Spinhaler, marketed by Fisons Limited. This small the user interacts with it almost always affects how wellDPI used a tiny impeller that drew energy from the it performs and ultimately how much drug is deliveredpatient’s inspiration to spin and whirl powder out of a (see Figure 1).pierced, standard gelatin capsule to create a respirableaerosol, thereby solving the coordination issues experi-enced by many users of pressurized metered dose inhalers Figure 1(pMDIs). Eliminating the need for bulky spacers also For the relationship between the user, the drugmade the Spinhaler easier to carry and more discreet dur- and the device to work successfully, the deviceing use, thereby encouraging greater patient acceptance. must be considered as a true interface.DPI development has moved on significantly since theSpinhaler’s launch and the inhaler market continues togrow. Asthma diagnoses are increasing, especially in therapidly-developing regions of the BRIC countries(Brazil, Russia, India and China), while opportunitiesfor pulmonary delivery are also emerging in varioustherapy areas, such as chronic pain relief and diabetesmanagement. The DPI also has great potential as a painfree alternative to injection, opening up new opportuni-ties in areas such as mass vaccination, where DPIs coulddeliver significant cost, safety and hygiene benefits.At present, DPIs are used primarily for asthma andchronic obstructive pulmonary disease (COPD) thera-pies. GlaxoSmithKline’s market-leading Diskus device Of course, the ultimate DPI would operate 100% effec-has set the performance benchmark for many years, but tively for every user. This is an idealized target, butthe emergence of new markets, together with the immi- unfortunately not one that the current state of the art isnent expiry of key drug and device patents, indicates that near to achieving. These following challenges must beDPI development has gained new impetus. However, sufficiently analyzed and understood before a new DPIdespite these commercial opportunities, the launch of a can enter the market successfully:
Understanding device performance device and user interaction from the start of the devel-The complex physics underlying a dry powder inhaler is opment process, otherwise the end result will not meetstill not well understood, making new device design a the usability goals.particular challenge. A DPI can be very difficult tomodel when the relationship between each drug and Regulatory driversdevice is unique,1 requiring numerous simplifications As DPI regulation is constantly evolving, a good deviceand assumptions to be made. However, such reduced design must not only meet current standards but alsoorder modelling is extremely useful in building an plan for future regulation by meeting published guid-understanding of the complex interaction between the ance. BRIC countries and others are also tightening reg-patient and the device, as well as between multi-compo- ulatory procedures in the face of both domestic andnent powder formulations and the convoluted airways international pressure, making entry to these huge mar-or “aerosolization engines” typically found within a kets even more challenging. Basing DPI design on exist-DPI. This complexity is underlined by current (and ing devices is not always an option, as many current andhighly successful) DPI efficiency rates of as little as successful DPIs would not gain regulatory approval if25% in controlled in vitro test conditions and perhaps put forward as new products today. Instead, R&D needseven lower in real use if the user compromises perfor- to innovate while planning ahead; understanding user’smance, for example, by inhaling too gently. current and future needs while also incorporating new advances in technology where appropriate. CautionaryThe influence of drug formulation tales of poorly designed DPIs abound within the sector,The powdered drug formulations used by DPIs offer but the example of the Ultrahaler, by Fisons Limited, ismany benefits: i) they are easier to manufacture and better known than most. Its innovative technology,store ii) once packaged, they are usually more stable and relating to both the device and its manufacture, couldconsistent than the fluid-based formulations used in not keep pace with regulatory change. After 19 years ofpMDIs. Dry powder also avoids environmental con- development and investment, and still no approval, thecerns related to pressurized canisters and propellants. development program was terminated.However, even though a powdered drug may be easier tohandle outside the DPI, moving the drug from bulk “Only” packagingstorage to device and then into the respiratory tract is Even though the high failure rate in DPI device designnot so simple. In a DPI, the correct dose must be deliv- underlines the difficulties inherent in the process, manyered every time, irrespective of the environment in companies continue to see the DPI as “packaging” andwhich the device is used, the way the patient inhales or consequently treat it with less respect than it deserves, orwhether the dose is the first or last within the course of indeed requires. If this mindset is the starting point fortreatment. Powdered drugs cannot suffer from preferen- an R&D program, then the process will undoubtedly fail.tial segregation during manufacture or storage, and oncein the device, must not be over sensitive to changes inthe environment, particularly at extremes of humidity. Technical challenges can be metThe technical challenge required to maintain such sus- GSK’s market-leading Advair Diskus device hastained control across a broad range of conditions is one remained essentially unchallenged for 15 years, a positionthat many R&D teams, perhaps unsurprisingly, find hard of dominance won by a highly innovative, robust andto meet. effective device designed to work with specific formula- tions. Such precision has been rewarded with significantUsability market share, but as key formulations come off-patent, newcomers show that this market can now be challenged.Usability has always been important but, under newguidance, has now become a regulatory imperative. To For example, in 2010, Sun Pharma announced the im-gain approval, a DPI must be safe; intuitive and easy to minent launch of a new DPI design, the Starhaler (seeuse correctly; and difficult to use incorrectly, a signifi- Figure 2), developed to work with a generic version ofcant challenge in itself, given that users span such a an off-patent formulation. Sun Pharma acknowledgedlarge range of age and ability. Usability will become the significant technical challenge ahead when it beganeven more important as new markets open up, for its development program. It responded by funding aexample, where there is no cultural “history” of inhaled comprehensive, reduced order mathematical model,2therapies or no time for users to develop or practice which allowed the R&D team to run virtual tests andtheir technique (e.g. if a DPI is used for a vaccination or analyses on the design parameters quickly and effec-to deliver a single dose therapy). As the technical chal- tively, and which could also be used in the developmentlenge differs for each application, development teams of future designs. By innovating rather than replicating,must understand—and in some cases predict—drug, Sun created a device that meets and exceeds current
standards and guidelines. As a result, the Starhaler able to create a respirable aerosol, the means to harnessachieves almost double the efficiency of current mar- this energy may not be obvious. The Spinhaler, andket-leading products, but perhaps more importantly, indeed many other capsule inhalers, tend to extend theachieves this high performance independently of the timeframe during which energy from the patient’squantity of inspiratory energy. If patients have impaired inhalation can be transferred into the powder formula-lung characteristics, for example, they will still receive tion. This is also true of multi-unit dose and reservoirthe correct dosage. DPIs that use swirling flow to extend particle pathAnother example of a successful DPI development is lengths and increase residence time, thereby increasingthe Aptar Prohaler (see Figure 3), which addresses the the total quantity of energy imparted into the formula-challenge of usability by achieving an extremely simpleusage sequence: “Open, Breathe-In, Close,” based onAptar’s “OBIC Technology.” Aptar Pharma wanted todevelop a multi-unit dose DPI that could meet the Figure 3requirements of the asthma market and was extremelyeasy and intuitive to use. It also had to be very difficult The Aptar Pharma Prohaler has an extremely simple usage sequence: Open, Breath-In,to use incorrectly. Consequently, this inhaler was devel- Close. (Photo courtesy of Aptar Pharma.)oped with the patient in mind. 3 Formative usabilityresearch was undertaken to establish suitably intuitiveuser-interaction principles, which included a combina-tion of visual and tactile feedback indicating correct use(see Figure 4). A strong visual language for the deviceplayed a key part in supporting the three-step operationand would appeal to user groups while being adaptablefor potential pharmaceutical partners’ varying brandrequirements. The result is a compact, distinctive devicewith an incredibly simple usage sequence.Scientists and engineers working on the Spinhaler real-ized that while there is ample inspiratory energy avail- Figure 2 The Sun Pharma Starhaler is an innovative device that achieves high performance, independent of the patient’s inspiratory energy. Figure 4 (Photo courtesy of Sun Pharma Advanced Research Company Ltd. and Cambridge This visualisation of Aptar Pharma’s Prohaler was Consultants.) created as part of a color study to explore visual language and brand differentiation. (Photo courtesy of Team Consulting and Aptar Pharma.)
tion and improving efficiency. Research into the energy Referencesrequired to disperse and aerosolize several milligrams of 1. Tibbatts J, Fuller A, Bowman N, (December 2011),typical powdered drug formulation indicates this is sev- TappiWhacky and the Golden Device – Part 1,eral orders of magnitude less than that available from a Proceedings from Drug Delivery to the Lungs 22patient.4 As collective understanding of the physics in Conference, 38-9.this area grows, it is likely that future passive DPIs willuse available energy more effectively and achieve higher 2. Harris D, Nandgaonkar A, Sangaiah G, Kane P, (Maydelivery efficiencies with greater consistency. 2008), A Mathematical Model to Optimize the Airway for a Dry Powder Inhaler; Respiratory Drug Delivery 2008, Vol 2: 451-6.Significant market opportunitiesA successful DPI device is one that meets the wide 3. Williams G, (October 2011), The Challenges inrange of technological challenges underpinning effi- Developing Today’s Pharmaceutical Drug Deliveryciency, usability, and regulatory approval, while also Devices, Drug Development & Delivery, Vol 11, No. 8:interacting effectively with a specific formulation. The 26-30.breadth and depth of skills required to deliver this level 4. Price R, Shur J, (May 2010), Powder Rheology: Aof performance are frequently underestimated by R&D New Technique to Predict the Performance of Inhaledteams. This lack of appreciation is one of the principal Powder Formulations, Proceedings from Respiratoryreasons so many DPI development efforts fail. Drug Delivery Conference, Book 1: 331-9.Substantial investment is required to develop a DPIwhich is technically robust, meets current and future Dav id Harris is He ad o f Re sp irato ry Drug De liv e ryregulatory standards, and which patients actively want to an d An d re w Po c o c k is a Man ag in g Co n sultan t w ithuse and can use with improved efficiency. However, Te am Co nsulting , Ltd ., Ab b e y Barns, Duxf o rd Ro adgiven the growth of inhaled drug therapies for a wider Ic kle to n , Cam b rid g e , CB10 1SX, UK , Te l: +44 1799range of conditions, the commercial and moral rewards 532700, d av id .h arris@te am -c o n sultin g .c o m , We b site :are clearly worth the investment. w w w.te am -c o nsulting .c o m .