Orally Inhaled & Nasal Drug Products

ORALLY INHALED & NASAL DRUG PRODUCTS: DELIVERY SYSTEMS, COMPONENTS AND SPECIALIST SERVICES FOR A GROWING INDUSTRY SECTOR

www.ondrugdelivery.com

OOINDPINDP MMarar 2010.indd2010.indd 1 222/3/102/3/10 08:58:5608:58:56 “Orally Inhaled & Nasal Drug Products: delivery systems, CONTENTS components and specialist services for a growing industry sector” Ingredient-specific particle sizing: reducing risk, This edition is one in the series of ONdrugDelivery cutting cost and saving time in preclinical publications. Each issue focuses on a specific topic inhalable formulation development within the field of drug delivery, and is supported by Dr Oksana Olkhovyk, Senior Scientist, and industry leaders in that field. Linda Batykefer, Marketing Manager Full contact information appears alongside each article. ChemImage Corporation 4-8 Contributing companies would be delighted to hear from interested readers directly. ONdrugDelivery Company Profile would also be very pleased to pass on to authors, or Coster Pharma 10 answer as appropriate, any queries you might have in relation to this publication or others in the series. Optimising drug and device together for

SUBSCRIPTIONS: novel aerosol therapies To arrange your FREE subscription (pdf or print) to Dr Manfred Keller, Executive Vice-President & CSO, ONdrugDelivery, contact and Dr Martin Knoch, President Guy Furness, Publisher PARI Pharma GmbH 12-16 T: +44 (0) 1273 78 24 24 E: [email protected] Automated actuations facilitating compendial testing of nasal spray and metered dose SPONSORSHIP/ADVERTISING: inhaler products To find out more about how your company can become Henrik G. Krarup, Vice-President, a participant in any of our sponsored issues, contact: Business Development Guy Furness, Publisher InnovaSystems, Inc 20-22 T: +44 (0) 1273 78 24 24 E: [email protected] Company profile MAILING ADDRESS: Catalent Pharma Solutions 24 ONdrugDelivery Publishing 48, Albany Villas, Hove, East Sussex BN3 2RW EnVision laser-based imaging system: United Kingdom fully characterises nasal- and dry powder-based systems PRODUCTION/DESIGN: Dr Séamus Murphy, Manager, Imaging Division, and Mark Frost Dr Tim Stephens, Imaging Systems Engineer www.frostmark.co.uk Oxford Lasers Ltd 26-28 “Orally Inhaled & Nasal Drug Products: delivery systems, components and specialist services Product profile for a growing industry sector” is published by Büchi’s Nano Spray Dryer 30 ONdrugDelivery Publishing.

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 acceptliability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

OOINDPINDP MMarar 2010.indd2010.indd 2 222/3/102/3/10 08:58:5808:58:58 OOINDPINDP MMarar 2010.indd2010.indd 3 222/3/102/3/10 08:58:5808:58:58 INGREDIENT-SPECIFIC PARTICLE SIZING: REDUCING RISK, CUTTING COST AND SAVING TIME IN PRECLINICAL INHALABLE FORMULATION DEVELOPMENT

In today’s fast-growing inhalables market, the availability of suitable, efficient and cost-effective means of gathering particle analysis data for pulmonary formulation is clear. In this article, Dr Oksana Olkhovyk, Senior Scientist, and Linda Batykefer, Marketing Manager, both of ChemImage Corporation, provide the latest about cutting-edge imaging tools for ingredient-specific particle sizing that ChemImage is putting at the disposal of the global pharmaceutical industry.

INTRODUCTION delivery via the lung is by no means dead, and many companies continue to develop inhaled There is an abundance of evidence supporting drug products.2 the fact that the markets both for respiratory drugs While the indications for many inhalable and respiratory drug delivery technologies are and nasal drug delivery products have been healthy, vibrant and growing. In recent years, somewhat limited to diseases such as allergic whilst pharmaceutical company product pipelines rhinitis and asthma, this is likely to change overall have been reduced, along with the number soon. Continuous research and development activities are gradually opening Oksana Olkhovyk, PhD up opportunities in new Senior Scientist “A MATERIAL ADVANCE IN THE T: +1 412-241-7335 ext 264 therapeutic areas. F: +1 412-241-7311 SPEED, COST AND LEVEL OF DETAIL Nasal drug delivery is E: [email protected] becoming more common due AT WHICH COMPANIES DEVELOPING to the potential for increased INHALABLE FORMULATIONS CAN drug uptake rates, improved bioavailability for certain drugs INVESTIGATE THEIR PRODUCTS’ (relative to oral dosing), and convenient administration. A PROPERTIES AND BEHAVIOUR”. growing number of nasally delivered, systemically acting of new drug approval applications submitted to drugs for a number of therapeutic areas are 3 regulatory authorities, pharmaceutical companies reaching the market or are in the pipeline. Linda Batykefer, MBA are continuing to pursue new delivery methods Other areas where new nasal and inhalation Marketing Manager for their drug products. The inhalation and drug delivery approaches could provide an T: +1 412 241 7335 ext 269 nasal products had combined sales exceeding alternative to current dosage forms (such as F: +1 412-241 7311 E: [email protected] US$22 billion in 2007 for treatment of asthma, intravenous administration) are crisis situations COPD, allergic rhinitis, influenza, migraine and (seizure and heart attack), motion sickness and osteoporosis, and for use in general anaesthesia. 1 psychotropic drugs.3 ChemImage Corporation 7301 Penn Ave One common trend is to develop respiratory Pittsburgh delivery technologies for drugs currently WHY PARTICLE SIZE MATTERS PA 15208 administered via injection. Despite some initial United States problems, such as the failure of Pfizer’s Exubera For nasal sprays and aerosolised products, www.chemimage.com (inhaled insulin), the concept of systemic there are two important measures of particle

OOINDPINDP MMarar 2010.indd2010.indd 4 222/3/102/3/10 08:58:5908:58:59 size. The first measurement is that of the aerodynamic particle size, which is traditionally measured via cascade impaction, and is the key method of predicting where particles will deposit in the nose, oesophagus or lungs. The second measure, the drug particle size, is an important determinant of the rate of dissolution and availability to sites of action within the nose (optimally approximately 10μm) or the lungs (<5μm). Therefore drug, or drug aggregate, particle size distribution (PSD) should be characterised in the formulation both within the primary container and within the aerosolised droplets.4

INGREDIENT-SPECIFIC PARTICLE Figure 1: Example particle size distribution (PSD) chart showing ingredient-specific PSD of two APIs. SIZING data is obtained from the combined information measurements for nasal spray suspensions.5 In The ability to gather general, basic of the optical and Raman chemical image. addition to investigating formulations for API information for a given formulation about See boxed text on page 8 for more particle size distribution, ISPS has been found aerodynamic particle size and particle size information on Raman chemical imaging and to be useful for the study of drug/drug and drug/ distribution is of course an essential starting Raman spectroscopy. excipient aggregates. point in successful product development. Raman spectroscopy is a very selective Particle size is directly related to deposition However, traditional methods only provide the vibrational technique and is often used in location in the body as well as bioavailability. most rudimentary, purely physical data and the pharmaceutical industry to identify drug Aggregates, which in effect bring about an cannot differentiate as to what a given particle polymorphs (different crystalline structures that increase in overall particle size, cause a number comprises chemically. are made of the same molecules, but exhibit of problems including: There is so much more useful information various crystal habits or packing). With the to unlock. In reality, inhaled formulations are ability to detect such small spectral differences, • clogging of the medical device rarely, if ever, comprised of just one ingredient. Raman spectroscopy is very comfortably able • deposition in the wrong or unwanted part of There will usually be at least two components; to differentiate between various materials in a the body the active pharmaceutical ingredient (API) pharmaceutical formulation, including the drug • changes in bioavailability and an excipient. Furthermore, the presence substance and various excipients (see figure 2). of more than two ingredients is becoming Ingredient-specific particle sizing is Readily available, high quality drug particle more commonplace as combination products especially useful for drug-specific particle sizing size data could provide the necessary information – containing two APIs plus an excipient – of both metered dose inhalers (MDIs) and nasal for conclusive in vitro bioequivalence (BE) are developed. spray suspensions. The method was initially comparisons of drug PSD, including PSD of It cannot be assumed that all ingredients have investigated in collaboration with the US dispersed and agglomerated API particles, as well similar physical characteristics, exhibit uniform FDA to achieve drug particle size distribution as the extent of agglomeration in the product.5 particle size distribution nor that they behave in the same way. Thus, information pertaining to the particle size of specific ingredients represents a significant advancement and holds many advantages. Ingredient-specific particle sizing (ISPS) is the technique offered by ChemImage which fulfils precisely this requirement for particle size data. The technique uses ChemImage’s unique technology combination of Raman chemical imaging, optical microscopy, and automated data gathering software to identify particles based on a unique chemistry (for example API versus excipient) and physical size information. Chemical information is based on the component chemistry identified by the unique Raman scattering. An example of ingredient-specific particle size distribution data for a sample formulation Figure 2: Raman Spectra of API components showing the ability of the Raman method containing two APIs is shown in figure 1. The to be used to distinguish the two API materials from one another.

OOINDPINDP MMarar 2010.indd2010.indd 5 222/3/102/3/10 08:58:5908:58:59 Obtaining drug particle size information With additional information related to drug regulatory terms, is a required measurement is important from a cost perspective. Prior particle size and material composition at their for in vitro testing of MDIs.6 A typical MDI to entering clinical trials, this additional disposal – information which was not easily formulation contains API, propellants and information can prove to be valuable, raising accessible in the past – innovators are even surfactants. Although PSD of the drug can be confidence and lowering risk of failure for in better equipped to design unique, hard-to- easily determined prior to the formulation, it is a vivo biostudies. duplicate formulations. challenge to establish it in the finished product. The value and importance of gaining ISPS has proven especially useful for The standard traditional apparatus for the in this information before taking the expensive innovative drug developers who are interested vitro determination of PSD information is the step of beginning clinical trials cannot be in combining multiple drug substances in one Anderson cascade impactor (ACI). A complete emphasised enough. formulation. While cascade impaction is useful ACI analysis includes introduction of the sample To give another example, in generic product for MDIs and DPIs when only one active into the ACI where particles are separated development, if drug PSD of the generic is ingredient is present, the situation becomes more on the basis of their aerodynamic size, this is found to be not equivalent to (or outside of complicated when two APIs are present. Raman followed by extraction of the drug substances acceptable variability thresholds of) the chemical imaging has been evaluated as a from the ACI plates, final filter, USP throat innovative product’s PSD, clinical trials can possible candidate to replace cascade impaction and mouthpiece adaptor, and finally performing be postponed until the acceptable drug PSD is as a tool to determine chemical identity PSD. quantitative chemical analysis by either HPLC reached – saving significant time and money for An example of such an application of ISPS or spectroscopy methods. generic companies. technology follows. The procedure is time consuming, labour Ingredient-specific particle sizing technology intensive and destructive. Presence of non- and service helps innovative drug developers to RAMAN CHEMICAL IMAGING volatile excipients in the formulation or a characterise and design their formulations better FOR PSD OF TWO APIS IN second API may complicate particle size and, further on in development, as part of batch COMBIVENT™ MDI characterisation even further. Analysis of the release testing. deposition profiles may indicate formulation With the increase in interest from The MDI is the most common device for issues such as agglomeration of APIs or innovative drug developers in inhalation and therapeutic aerosol delivery, second only to physicochemical stability (polymorphism, nasal drug delivery, methods that characterise tablets among self-medicated dosage forms.6 hydration) after actuation. Furthermore, a large formulations without destroying the sample The PSD of the drug substance in the aerosol variability in results has been observed between are increasingly needed. plume is a very important parameter and, in different operators and different ACI units. As a consequence, there is a high demand for the replacement of the ACI with an alternative A B technique capable of concurrently performing PSD determination and chemical identification. 6 In a previous study, Raman chemical imaging (RCI) was evaluated as a method for identifying two API species on cascade impaction plates and characterising drug interaction in Combivent® Inhalation Aerosol (Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, United States), an MDI sample containing two APIs. RCI successfully identified each API particle and the total number of particles and PSD for each API and PSD of aggregated API particles were reported. 6 ChemImage had successfully applied RCI to measure ingredient-specific size distribution C in formulated nasal sprays and aerosols. This Figure 3: A) Brightfield investigation was initially reported in 2005; reflectance image, 50x significant progress has been made since objective, B) Brightfield/ to optimise the technique and enhance the Raman chemical image capabilities of RCI for the pharmaceutical overlay, C) Associated Raman spectra of API industry. Issues have been addressed related to particles. Particle size automation, image processing, and particle size range 3.3-4.7 µm. analysis by applying an automated method of data collection and analysis of fused RCI and brightfield imaging.7,8 A new, patent-pending image processing method has been developed to evaluate each particle in the field of view individually, rather than collectively.9 Using this image processing technique, the original Combivent RCI data reported by Guo et

OOINDPINDP MMarar 2010.indd2010.indd 6 222/3/102/3/10 08:58:5908:58:59 al was revisited. API 1 (albuterol sulfate) and API the drug properties within the formulation. RCI TO OUTSOURCE RESEARCH OR 2 (ipratropium bromide) are presented as purple provides drug particle sizing and distribution PURCHASE EQUIPMENT? and blue in the brightfield / Raman binary image information and also provides information overlay (figure 3). Intensity maps were developed about aggregates. What is the drug PDS for ChemImage typically offers its ISPS for each API using an iterative threshold process. each API? What particles are aggregating? services on a contract research basis. Once the particle map is produced, a feedback Are drug particles aggregating or are drug and However, it is also possible to purchase the loop is initiated which confirms the chemical excipient particles aggregating to one another? equipment necessary to do this work from identity against the Raman spectrum and validates Is this related to the device delivery or does this ChemImage. This is especially useful for the particle size against the brightfield optical happen in the bulk formulation? organisations which plan to do a significant image. This individual particle identification ISPS can be used during product development, amount of drug PSD testing in the future. approach allows for a more accurate and reliable specifically formulation development, as well as Larger volumes of sample testing may drug PSD measurement, effectively addressing R&D for novel or existing formulations and make purchase of the equipment more cost concerns of accurate size measurements in the during manufacturing for batch release testing. effective. Purchase of the equipment is a previous publications.5 This combined image Possessing this information could ultimately capital expense, but also offers customised analysis approach helps to avoid the issue of over- result in, for example, faster ANDA filing, or options for multiple imaging platforms or under-sizing particles due to Raman signal more efficient and successful clinical trials. including microscopic Raman and Near-IR or intensity – which is related to size of the particle. With a better understanding of the formulation, Fluorescence chemical imaging capabilities companies can mitigate risk in a number of in addition to basic optical microscopy and CHEMIMAGE’S SERVICES: HOW steps during development for approval. Raman spectroscopy. AND WHEN? The earlier in formulation development this technique is employed, the better the chances ABOUT CHEMIMAGE: The ISPS services offered by ChemImage and of identifying incorrect drug particle size described here represent a material advance in the distribution, or aggregation issues. Founded in 1994 and headquartered in speed, cost and level of detail at which companies If being used as part of a BE study, this method Pittsburgh, PA, US, ChemImage provides developing inhalable formulations can investigate can also be used to gain an understanding of the revolutionary Raman, Near-Infrared and their products’ properties and behaviour. innovator drug product. This testing can be done Fluorescence chemical imaging technologies The major advantage of utilising these early on before the innovator or generic product is for chemical and biological applications contract services is the ability to understand even in development, or it can be done in parallel. in numerous global industries including

OOINDPINDP MMarar 2010.indd2010.indd 7 222/3/102/3/10 08:59:0008:59:00 3. The Growing Market for Nasal Drug Delivery. Q: What is Raman Chemical Imaging? (approaching 350 nm for high signal-to-noise Kock, Melissa. 2003, PharmaTech, pp. 1-3. images) and high Raman spectral resolution. A: Raman chemical imaging builds on the The no-moving-parts approach employed to 4. U.S. Department of Health and Human ability of spectroscopy by adding a spatial construct Raman chemical images enables fusion Services, Food and Drug Administration, context to the chemical information provided. of optical and Raman chemical imaging data. Center for Drug Evaluation and Research. Raman Chemical Imaging (RCI), a method Fused optical/Raman images are used to guide Draft Guidance for Industry, Bioavailability that combines the capabilities of molecular the size measurements, differentiation between and Bioequivalencce Studies for Nasal Aerosols spectroscopy and advanced digital imaging, drug aggregates and individual particles. This and Nasal Sprays for Local Action. 2003. details material morphology and composition approach helps eliminate problems often seen with a high degree of specificity in a non- with morphologically-directed, confocal Raman 5. Doub, William H., et al. Raman chemi- contact, non-destructive manner. spectroscopy, which requires precise, repeatable cal imaging for ingredient-specific particle stage translation. size characterization of aqueous suspension A Raman chemical image provides a Raman nasal spray formulations: A progress report. spectrum at each pixel in the image, provid- Q: What is Raman spectroscopy? Pharmaceutical Research. May 2007, Vol. 24, ing spatially resolved Raman spectroscopic 5, pp. 934-945. information. Interrogation of individual pix- A: This is a spectroscopic technique used to study els assists in the interpretation of the data. vibrational, rotational, and other low-frequency 6. The potential use of Raman imaging for deter- Presence or absence of API within a field modes in a sample system. It relies on inelastic mination of the particle size distribution (PSD) of view is determined by whether or not scattering, or Raman scattering, of monochromatic of active pharmaceutical ingredients (APIs) the Raman spectral features characteristic of light, usually from a laser in the visible, near in metered-dose inhalers. Guo, Changning. the drug are present. Imaging allows one to infrared, or near ultraviolet range. The laser light s.l. : The Third International Conference on understand size, shape, and spatial distribu- interacts with phonons or other excitations in Advanced Vibrational Spectros, 2005. tion of chemical components which provides a the sample system, resulting in the energy of the number of advantages of simple Raman spec- laser photons being shifted up or down in energy. 7. Ingredient-specific particle sizing for batch troscopy, and in particular drug particle sizing The shift in energy gives information about the comparison to analyze the drug PSD in aque- for nasal and pulmonary drug products. phonon modes in the system. ous nasal spray formulations. Priore, Ryan, Olkhovyk, Oksana and Klueva, Oksana. Lisbon, In the wide-field RCI approach, digital images Scattered photons from the illuminated sample Portugal : Respiratory Drug Delivery (RDD) are acquired at pre-defined Raman spectral spot are collected with a lens and sent through Europe Conference, 2009. regions, by imaging an area through an electro- a monochromator – or in the case of imaging optically controlled, liquid crystal tunable filter an imaging spectrometer. Wavelengths close 8. Ingredient-specific particle sizing for batch (LCTF) which serves as an imaging spectrometer. to the laser line, due to elastic Rayleigh comparison to analyze the drug particle size dis- The RCI microscope simultaneously scattering, are filtered out while the rest of the tribution in aqueous nasal spray formulations. provides diffraction-limited spatial resolution collected light is dispersed onto a detector. Priore, Ryan, et al. Los Angeles, California : American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, 2009. pharmaceutical, anatomic pathology, forensics ACKNOWLEDGEMENTS: and threat detection. 9. Michael Fuhrman, Ryan Priore, Oksana The ChemImage workforce of researchers, • Dr. Changning Guo, FDA, for providing the Klueva, Oksana Olkhovyk. Automation of software designers, hardware developers, original data. Ingredient-Specific Particle Sizing Using Raman scientists, business analysts and administrative • Brittney Higgs, ChemImage, for preparing Chemical Imaging. 12/684,495 U.S., January 8, support has tripled in the new Millennium, as images for print. 2010. Patent Application. more and more industries begin to understand and integrate the power of chemical imaging as REFERENCES: 10. Drug Delivery Markets, Vol III: Pulmonary a tool for realising their vision. Delivery Systems. s.l. : Kalorama Information, ChemImage currently has an extensive 1. Espicom. Emerging Opportunities in 2007. patent portfolio including 75 issued US Inhalation & Nasal Spray Generic Drugs. s.l. : patents, 12 allowed patents and has over 100 Espicom Business Intelligence, 2008. 11. Spectroscopic Investigations into the US and foreign patents for technology and 2. Inhalable drugs on the Launch Pad: Will Structure of Carrier-Based Dry Powder Inhaler methodology advancements across all of our They Take Off? Greb, Erik. April 2008, Formulations. Kinnunen, H., et al. Edinburgh : lines of business. Pharmaceutical Technology, pp. 48-55. Drug Delivery to the Lungs 20, 2009. 120. IN WHICH EDITION SHOULD YOUR COMPANY APPEAR? WWW.ONDRUGDELIVERY.COM

OOINDPINDP MMarar 2010.indd2010.indd 8 222/3/102/3/10 08:59:0008:59:00 OOINDPINDP MMarar 2010.indd2010.indd 9 222/3/102/3/10 08:59:0108:59:01 COMPANY PROFILE – COSTER PHARMA

Coster is a leading provider of both aerosol components and filling machines for the pharmaceutical, personal care and cosmetics industries. Founded in the early 1960s, now with an annual turnover of €150 million, Coster has more than 40 years’ experience in the design and manufacture of high-quality packaging systems.

Coster is the sole company worldwide supplying integrated aerosol and spray solutions, including: • MDI valves and inhalers for HFA and CFC • 20 mm & one-inch valves and actuators • Bag-On-Valves (BOV) and actuators • Filling lines for inhaled, nasal, oral, and topical products

Coster’s robust and reliable technology allows it to meet the pharmaceutical industry’s stringent quality standards and product safety features, while maintaining competitive prices.

Coster’s R&D Centre offers formulation and re-formulation services for selected aerosol and spray OTC products. Customised aerosol courses can be hosted in-house or on-site. ISO 8 CLEAN ROOM COSTER CERTIFICATIONS Coster has implemented an ISO 8 Clean ISO 9001:2008 COSTER PHARMA PRODUCT RANGE Room where dedicated pharmaceutical ISO 15378:2006 Coster’s range includes the following products: components are manufactured. ISO 8 CLEAN ROOM • MDI valves: for HFA and CFC Type III DMF for BOVs • MDI asthma inhalers: for HFA and CFC Production takes place in accordance • Salus nasal actuator: for sea-water solutions with ISO 15378:2006, an international FILLING MACHINES • Nasal actuators & spray pumps: for different certification which encompasses ISO 9001 Coster Pharma has more than 40 years’ nasal applications procedures and cGMP guidelines applied experience in the design and manufacture • Bag-On-Valves (BOV): for liquids, gels and to Primary Packaging Materials for of high-quality filling machines. Coster’s viscous products Medicinal Products. range includes semi-automatic machines for laboratory use (20 cans/min) to fully- automatic lines (up to 250 cans/min).

Bianca Cavalli Sales & Marketing Manager Coster Pharma T: +39 02 6361 6254 F: +39 02 2900 6055 E: [email protected]

Coster Tecnologie Speciali S.p.A. Corso Como 15 20154 Milano Italy

www.coster.com www.costerpharma.com

OOINDPINDP MMarar 2010.indd2010.indd 1010 222/3/102/3/10 08:59:0208:59:02 PHARMACEUTICAL AEROSOL COMPONENTS AND FILLING MACHINES

COSTER GROUP New 20 DPH Metering Valve HEADQUARTERS • MDI metering valve [email protected] Tel. +39 026 361 61 • Suitable for HFA & CFC-based formulations Fax +39 022 900 6706 • Stem block Ø : 3.18 mm & 2.8 mm MACHINERY DIVISION • Available dosages: 25 / 50 / 63 / 100 μl [email protected] Tel. +39 02 339 561 • Plastic components and gaskets Fax +39 02 339 56372 are EP/USP compliant

ARGENTINA Coster Packaging S.A. 2-piece Asthma Inhaler [email protected] Tel. +54 (2322) 466 206 • For aluminium cans Ø 20 mm, 60 mm height Fax +54 (2322) 496 664 • Suitable for 20DPH & 20DR aerosol valves FRANCE Coster S.à.r.l. • Spray holes for HFA or CFC propellant [email protected] • Colour code according to formulation Tel. +33 (1) 6467 9655 or customer requirements Fax +33 (1) 6467 0404 • Can be customized with company logo GERMANY Coster Tecnologie Speciali GmbH [email protected] Tel. +49 (7243) 5483-0 Fax +49 (7243) 5483-54 Salus nasal actuator HOLLAND Robertpack Engineering B.V. for sea-water [email protected] solutions Tel. +31 (38) 4652 080 Fax +31 (38) 4657 076 • For children & adult use INDIA • 2 different delivery rates available Coster India Packaging Pvt. Ltd. • Suitable for BOV3 Bag-On-Valves [email protected] Tel. +91 (124) 404 3701 (for undercup pressurization with air Fax +91 (124) 404 3704 or nitrogen)

SOUTH EAST ASIA • Can be Gamma irradiated Coster Asia Pacific Pte. Ltd. [email protected] Tel. +65 9139 1468 Pharmaceutical Filling Machines Fax +65 6891 3687 • Automatic ﬁ lling lines (from 10 to 250 CPM) SPAIN • Semi-automatic machines and laboratory Costertec S.A. equipment [email protected] Tel. +34 (93) 859 1038 • Suitable for both single and double Fax +34 (93) 859 3510 stage ﬁ lling UNITED KINGDOM • Manufactured and tested using HFA Coster Aerosols Ltd. 134 a as a standard [email protected] Tel. +44 (1438) 367 763 • AISI 316 L stainless steel construction Fax +44 (1438) 728 305 • 100% suitable for all current aerosol propellants USA Coster USA Inc. [email protected] Tel. +1 (847) 760 6040 Fax +1 (847) 760 6035 www.costerpharma.com

OOINDPINDP MMarar 2010.indd2010.indd 1111 222/3/102/3/10 08:59:0508:59:05 OPTIMISING DRUG AND DEVICE TOGETHER FOR NOVEL AEROSOL THERAPIES

In certain inhalable product delivery applications, the use of a nebuliser can bring benefits compared with using MDIs or DPIs. In this article, Dr Manfred Keller, Executive Vice-President and CSO of PARI Pharma, and Dr Martin Knoch, President, outline the case for nebuliser use and provide examples of how PARI Pharma has developed tailored versions of its nebuliser technology platform, eFlow®, in parallel with different pharmaceutical products, for use by various patient groups and in the treatment of a number of diseases.

ADVANTAGES OF NEBULISED agency (EMA) via a separate new drug application DRUG THERAPY (NDA), nebulisers receive market clearance in the US via a 510(k) premarket notification (CDRH When treating various respiratory diseases, Guideline 784), and by CE marking in the EU. inhalation of aerosols to the lungs is the preferred The nebuliser regulatory pathway is advantageous, route of administration of pharmaceutical since inhaled liquid formulations can be tested and compounds. Unlike pressurised metered dose clinically evaluated faster and more economically inhalers (pMDIs) and multidose dry powder than pMDIs and DPIs. Regulatory approval is inhalers (DPIs), nebulisers can be used across a usually less burdensome and costly. wide dose range (μg- up to gram-range) without loss of overall delivery performance. Unlike ADDRESSING UNMET NEEDS single-breath administration with pMDIs and WITH AN ADVANCED AEROSOL DPIs, patients take treatment during multiple PLATFORM: EFLOW® consecutive spontaneous breathing manoeuvres. Further, the treatment requires only minimal Looking ahead, the acceptance of nebulisers Dr Manfred Keller coordination and effort in comparison with in a competitive market will require development Executive Vice President and CSO pMDIs or DPIs. of improved devices which meet patients’ and T: +49 89 742 846 44 Patients with severe disease who experience caregivers’ needs. Special consideration to E: [email protected] impaired breathing and co-ordination capabilities superior delivery efficiency with consistent droplet can master the use of a nebuliser. Various size distribution and dosing during treatment is drug compounds can be nebulised, including essential along with treatment times significantly peptides (e.g. Colistin), proteins (e.g. alpha-1 reduced compared with current approved nebuliser antitrypsin), or antibiotics (e.g. tobramycin), therapies. Further, nebuliser features that address and drugs with poor lung tissue penetration ease of use, small size, portability, silent operation, (Ciclosporin A). Compared with individual and simple cleaning will help improve patient actuations from a pMDI or DPI, nebulisers acceptance to nebuliser therapy. generate a large amount of fine aerosol which With the objective of fulfilling these require- ® enables the drug to be more evenly distributed ments, PARI Pharma developed the eFlow Dr Martin Knoch to the large surface area of the lungs (best device platform which utilises a perforated, President illustrated by “wetting” a tennis court area). vibrating membrane technology to generate liq- T: +49 89 742 846 20 Nebulisers are particularly useful for those uid aerosols of distinct droplet sizes. The eFlow E: [email protected] drugs which require high dose deposition to the device platform has a significantly higher deliv- lungs, or for distinct patient populations, such ery efficiency than established jet, ultrasonic, PARI Pharma GmbH as those with severe disease, young children, the or general purpose vibrating-mesh nebuliser Lochhamer Schlag 21 82166 Gräfelfing elderly, or mechanically-ventilated patients in a systems used with current approved nebulised Germany hospital intensive care unit. drug products. The higher delivery efficiency While nebulised drugs receive marketing allows for dramatically shorter inhalation times www.paripharma.com authorisation from the US FDA or European and a substantial reduction of drug volume and

OOINDPINDP MMarar 2010.indd2010.indd 1212 222/3/102/3/10 08:59:0608:59:06 PARI PHARMA`S ADVANCED DELIVERY PLATFORMS

Platforms for Platform for Lower Respiratory Delivery Upper Respiratory Delivery

Open system Platform Drug Specific Platform Drug Specific Platform Drug Specific Platform Drug Specific Platform Cystic fibrosis (CF) Orphan indications Large market indications Intensive care Nasal delivery CF, bronchiectasis, Pediatric asthma, severe VAP, HAP, RDS Sinusitis AAT deficiency, asthma, COPD bronchiolitis obliterans

eFlow rapid Investigational Investigational Investigational Investigational (In EU, AUS, LA) eFlow eFlow CS eFlow Inline Vibrent (Closed System) Trio Investigational (disease intervention eFlow neos program In USA) (neonatal system)

Figure 1: eFlow® Technology platforms: lower respiratory system delivery (eFlow®) and upper respiratory system delivery (Vibrent®)

dose, as higher drug concentrations are feasible is attractive for many new and proven drugs European CF patients. The inhalation of TOBI® and less drug is wasted. as the drug and device are developed and (tobramycin) with eFlow rapid has been shown Where the approved nebulised drugs of optimised together and approved via mutually to be safe and effective based on experience from today focus on volume fills of 2-5 ml (7 min up conforming labels. Further, eFlow Technology daily practice and a clinical study demonstrating to 30 min range), the targeted formulations of is versatile with respect to target droplet size comparable tobramycin blood plasma levels and the future in eFlow Technology devices will be (mass median diameter (MMD) 2.5 μm up sputum concentrations.3 in the 0.5-2 ml range (2 min up to 4 min) which to 5.0 μm) and offers customisation options encourage improved patient adherence. This for lower (lung) and upper (sinus) respiratory PIONEERING CHARACTERISATION feature, qualifies eFlow Technology devices for drug delivery. eFlow Technology devices are OF NEBULISED DRUG PRODUCTS the delivery of expensive drugs and in situations intended for home use as well as the hospital when long treatment times would be a strong setting, including critical care settings, and Guidelines issued by the FDA and EMA on deterrent to patient compliance. are designed as a hand-held version, or as a nasal and orally inhaled drug products contain Based on numerous studies and initial market stationary configuration for use with ventilators testing specifications, but do not disclose experience, eFlow Technology has proven to be (see figure 1). Certain eFlow Technology how to carry out such tests. An assessment robust and suitable for nebulisation of many devices can incorporate an electronic treatment of nebuliser systems cannot be done with a drug products including fragile molecules such monitoring function to measure compliance. simple gravimetric measurement, but requires as rhDnase (Pulmozyme®), alpha-1 antitrypsin, the quantification of the drug content delivered siRNA, DNAzyme, as well as novel liposomal PROVEN TECHNOLOGY under simulated breathing conditions. drug formulations.1 WITH EXCEPTIONAL PATIENT The CEN nebuliser standard4 describes a ACCEPTANCE simplified type-testing method for the head- VERSATILITY FOR CUSTOMISED to-head comparison of nebuliser systems using CONFIGURATIONS An eFlow Technology device called eFlow® an aqueous sodium fluoride surrogate solution. rapid was designed to deliver comparable doses However, since physico-chemical properties eFlow Technology devices are able to of currently available nebulised drugs used by of solutions and suspensions can deviate deliver a wide range of drug volumes (0.5-8 cystic fibrosis (CF) patients and approved for use substantially from a sodium-fluoride solution, ml) and dosages (0.01-1000 mg) and have been with jet nebulisers, such as the PARI LC PLUS. such results do not reflect specific drug/device customised to meet with dedicated applications Since its launch in Europe in 2005, eFlow rapid interactions5, especially when delivered using and patient requirements.2 eFlow Technology has gained a market share of about 75% amongst novel aerosol generation technology.

OOINDPINDP MMarar 2010.indd2010.indd 1313 222/3/102/3/10 08:59:0608:59:06 Figure 2: PARI Compas TM Breath Simulator test set-up Figure 3: Climate box with New Generation Impactor (NGI) test set-up

Thus, the PARI Compas™ Breath Simulator impactor as well as humidity and temperature of generated by a nebuliser remain relatively stable.8 (figure 2) is used for aerosol characterisation the air entrained into the nebuliser (see figure 3). Adequate in vitro testing of a specific drug/ testing that allows measurement of the delivered This set-up allows for the investigation of various device combination is critical to accurately charac- dose of a nebuliser with breath simulation adjusted effects on the in vitro deposition performance of terising and identifying such complex interactions to realistic patient breathing conditions. The nebulised products, including effects caused by before proceeding into costly clinical trials. methods used for nebuliser testing (wet aerosols) ambient humidity and temperature as observed are substantially different from those established with hygroscopic drug compounds.8 FROM BENCH TO CLINIC: DSCG for pMPIs and DPIs (dry aerosols). PARI Pharma was a key contributor to the development of UNDERSTANDING DRUG AND In vitro assessment of various DSCG delivery these relevant testing standards which have been DEVICE INTERACTIONS systems, for the treatment of asthma, revealed implemented for in vitro testing. extremely poor performance of Intal® pMDI and Deposition of aerosolised drug into the lungs DPI systems, which led to the conclusion that ACCURATE ASSESSMENT OF is determined by different factors, i.e. patient inhaled DSCG may have been underrated in its DROPLET SIZE factors and drug/device factors. Individual lung therapeutic effect.8 anatomy and patient breathing manoeuvre have We hypothesise that in order to achieve a Measurement of nebuliser droplet size is typi- a major impact on drug deposition. In addition, remarkable therapeutic effect in the treatment cally conducted using two different methods: laser the design, functionality and quality of the of asthma, a much higher DSCG dose will be diffraction or cascade impaction with an Andersen device and the interaction of drug formulation required at the target site, specifically to the mast cascade impactor (ACI) or the Next Generation and device play an important role. cells located in the lung periphery. A clinical study Impactor (NGI). The latter is more suitable since The droplet size can be heavily influ- was designed to prove this hypothesis comparing its calibration at 15 l/min allows a more accurate enced by the viscosity and surface tension of standard inhaled corticosteroid therapy with an measurement of nebulised aerosols.6 the drug formulation. Hygroscopic drugs, such isotonic DSCG solution administered via a small In order to avoid droplet evaporation and as di-sodium cromoglycate (DSCG) and colis- droplet eFlow Technology device in children distortion of the size distribution, proper assessment timethate may absorb water from the ambient above six months of age. Preliminary findings of the droplet size requires cooling of the impactor air causing particle growth within milliseconds. indicate that the DSCG administered via a small for wet aerosols (nebulisers) to equilibrate the Thus, the fine particle dose (respirable particles droplet generating investigational eFlow may be temperature of the emitted aerosol.7 To this end, < 5 μm) of a pMDI or DPI can be reduced sig- equally potent due to a higher and more distally PARI Pharma developed a climate box allowing nificantly when hygroscopic drug is exposed to the deposited lung dose, compared with twice daily adjustment of the temperature of the cascade humidity saturated human airways, while droplets inhaled steroids as no therapeutic difference

Lung deposition [mg] Sputum concentration [mg/l] Cmax [mg/l] Product TOBI Tobramycin PARI TOBI Tobramycin PARI TOBI Tobramycin PARI All patients 45.4 46.0 2.27 2.59 1.65 1.29 adults 46.8 45.6 2.65 2.67 1.81 1.21 children 44.1 46.4 1.99 2.5 1.52 1.36

Figure 4: Lung deposition of two 99mTC-DTPA labeled tobramycin solutions investigated in a crossover design study in CF patients (n = 16, 8 children, 8 adults) after inhalation of TOBI (300 mg/5 ml) via the PARI LC PLUS and Tobramycin PARI (150 mg/1.5 ml) 11 via an investigational eFlow nebuliser. Data on sputum concentration and Cmax were obtained from a 28-day safety study in CF patients (n = 76, 38 children, 38 adults).12

OOINDPINDP MMarar 2010.indd2010.indd 1414 222/3/102/3/10 08:59:0708:59:07 could be observed after three and six months of Another optimised drug/device combination DRUG PRODUCTS WITH UNIQUE treatment, respectively.8 currently in clinical development is a low-volume, PROPERTIES: INHALED LIPOSOMAL high-concentration Tobramycin PARI inhalation CYCLOSPORINE A MATCHING DRUG FORMULATION solution (150 mg/1.5 ml) for nebulisation via AND DEVICE: INHALED ANTIBIOTICS an investigational eFlow nebuliser. The goal Over the past several years, PARI Pharma has of this development was to decrease CF patient developed a liposomal cyclosporine A (L-CsA) Drug formulations and the delivery device treatment burden by shortening the inhalation inhalation formulation as its lead proprietary can be mutually adapted and matched for optimal time to about one quarter, compared with TOBI drug product candidate. The formulation characteristics to reach the desired therapeutic target. (tobramycin 300 mg/5 ml) approved for delivery consists of unilammelar liposomes, equal to or Reformulation of known and proven compounds via the PARI LC PLUS jet nebuliser. less than 100 nm in size, that demonstrated a in a liquid format are commercially attractive as Data summarised from a gamma deposition very favourable lung tissue penetration as well they present a relatively low development risk for and safety study (figure 4), demonstrated as excellent mucosal tolerability in preclinical potential drug product candidates and, thus, have that nebulisation time could be reduced from testing. L-CsA has undergone a successful become a preferred pathway for the development approximately 16 minutes to four minutes with Phase Ib lung deposition study13 and is currently of new inhalation products. a similar deposited dose. Due to the higher being investigated in a multicenter, randomised, The monobactam antibiotic Cayston® delivery efficiency of the investigational eFlow double-blind, placebo-controlled Phase IIb study (aztreonam for inhalation solution 75mg) from device, only 150 mg (instead of 300 mg) of for the prevention of bronchiolitis obliterans in Gilead Sciences was recently approved as a tobramycin was needed to obtain comparable lung transplant recipients. treatment to improve respiratory symptoms in lung deposition11 and sputum concentration, cystic fibrosis (CF) patients with Pseudomonas based on data from a safety study conducted A UNIQUE CONCEPT FOR aeruginosa (P. aeruginosa). in 76 CF patients (38 adults and 38 children) PRODUCT PROTECTION: PARI Pharma contributed pharmaceutical over 28 days.12 EFLOW® CLOSED SYSTEM

formulation development, analytics and aerosol The lower Cmax indicates less drug was characterisation to optimise the Cayston systemically absorbed which may reduce Another major advantage of the eFlow Tech- formulation with the device. The treatment the potential for undesired ototoxic and nology platform is the option to use a proprietary time for this novel inhaled antibiotic therapy nephrotoxic side effects. The shorter inhalation blow-fill-seal ampoule containing the ready to use is 2-3 minutes compared with the current first- time could help to improve patient compliance liquid inhalation formulation. A nebuliser with line therapy, which requires 15-20 minutes and therapeutic efficacy from a long-term an integrated single-dose ampoule may be ideal per dose.10 perspective. for specific indications where ease of handling

OOINDPINDP MMarar 2010.indd2010.indd 1515 222/3/102/3/10 08:59:1008:59:10 and protection against the use of unauthorised scale manufacturing. Substantial know-how in (FPD) of Disodium Cromoglycate (DSCG)”, medications are key factors to the regulatory formulation development, analytics and aerosol Proc. Respir. Drug Delivery Europe, 307-310. pathway. In addition, this patented ampoule design characterisation, all in compliance with GMP allows the prevention of generic alternatives even requirements and accompanied by a state-of- 9. Moeller, A; Spescha, H; Knauer, N; Inci, after the original drug patents expire. the-art QA, address all needs for the successful D; Wildhaber, J (2008), “Efficacy of an iso- The eFlow closed system highlights three approval of nebulised drug products. tonic small droplet size nebuliser DSCG on unique design features: Development partnerships with small and large asthma control in children”, European Respir. (1) A single dose ampoule that becomes an pharma companies, and the recent approvals of Soc. Annual Meeting (ERS), Berlin, Germany, integral part of the device Cayston in the eFlow Technology device, Altera®, October 4-8. Poster # 3958. (2) the ampoule is required to operate the device demonstrate PARI Pharma’s ability to provide (3) the ampoule is automatically opened when the full spectrum of knowledge and networks, 10. Retsch-Bogarart, GZ; Quittner, AL; Gibson, locked into the device.14 including clinical and regulatory support and RL; Oermann, CM; McCoy, KS; Montgomery, services, required to transfer a project idea into a AB; Cooper, PJ (2009), “Efficacy and safe- Thus, a customisation of nebulised drug therapy drug and device combination product. ty of inhaled Aztreonam-lysinate for airway regarding age or disease or application-specific PARI Pharma has several proprietary clinical Pseudomonas Aeruginosa in cystic fibrosis”, requirements can be adequately addressed. development programs ongoing either for licensing Chest 135, 1223-1232. in later stages or marketing on its own. DRUG DELIVERY IN A VENTILATOR 11. Denk, O; Coates, AL; Leung, K; Green, CIRCUIT: EFLOW® INLINE REFERENCES M; Chan, J; Ribeiro, N; Charron, M; Keller, M (2009). “Lung delivery of a new tobramycin Aerosol delivery to mechanically ventilated 1. PARI publication list on www.paripharma.com nebuliser solution (150 mg/1.5 mL) by an inves- patients is associated with high drug losses, poorly tigational eFlow nebuliser is equivalent to TOBI reproducible delivered doses (DD) to the patient, 2. Knoch, M & Keller, M (2005),”The custom- but in a fraction of time”, J. Cystic Fibrosis 3, and rather low delivery efficiency (7.7% mean ised electronic nebuliser: a new category of liq- suppl. 2, 66 (ECFC abstract/poster 264). DD at the end of the endotracheal tube). PARI uid aerosol drug delivery systems”, Expert Opin. Pharma has developed a nebuliser configuration Drug Deliv. 2 (2), 377-390. 12. Griese, M; Kappler, M; Eismann, C; Mazurek, with an improved performance for ventilator H; Denk, O; Goedings, P; Tillmanns, S; Keller, M use characterised by a high dose consistency 3. Hubert, D; Leroy, S; Nove-Josserand, R; Murris- (2009), “Pulmonary delivery of tobramycin by independent of different ventilators and ventilation Espin, M; Mely, L; Dominique, S; Delaisi, B; an investigational eFlow electronic nebuliser parameters.15 This new eFlow Inline device may Kho, P; Kovarik, JM (2009): “Pharmacokinetics saves 50% of the drug and results in equivalent serve to improve the treatment of ventilator and safety of tobramycin administered by the or improved tobramycin safety levels in plasma associated pneumonia (VAP) using, for example, PARI eFlow® rapid nebuliser in cystic fibrosis”, and sputum”, Pediatr. Pulmonol. 32, 300 (NACF nebulised antibiotics in critical-care settings. J. Cystic Fibrosis 6, 332-337. abstract/poster 252).

A NOVEL UPPER RESPIRATORY 4. CEN-Nebuliser Standard EN 13544-1 (2002), 13. Behr, J; Zimmermann, G; Baumgartner, R; DRUG DELIVERY CONCEPT: VIBRENT® “Respiratory therapy equipment - Part 1: Leuchte, H; Neurohr, C; Brand, P; Herpich, C; Nebulising systems and their components”. Sommerer, K; Seitz, J; Menges, G; Tillmanns, The Vibrent was developed to offer a new S; Keller, M (2009), “Lung deposition of a treatment option for patients suffering from chronic 5. Keller, M; Jauernig, J; Lintz, F-C; Knoch, M liposomal cyclosporine A inhalation solution in rhino sinusitis (CRS) affecting about 5-10 % (2002), “Nebuliser nanosuspensions: Important patients after lung transplantation”, J. Aerosol of the population worldwide. The Vibrent is a device and formulation interactions”, Proc. Med. Pulm. Drug Delivery 22 (2), 121-129. novel device using pulsating airflow and enabling Respir. Drug Delivery VIII, Tucson, Arizona, nasal drug delivery to the osteomeatal area and USA, 197-206. 14. Gallem, T; Tservistas, M; Uhlig, M; Waldner, the paranasal sinuses as revealed from a gamma R; Seemann, S; Keller, M; Knoch, M (2009), deposition study in 16 volunteers. Of the emitted 6. Marple, VA; Olson, BA; Santhanakrishnan, “Evaluation of an ampoule-based nebuliser sys- aerosol, 71.5 ± 13 % deposited in the nose and 7.1 K; Roberts, DL; Mitchell, JP; Hudson-Curtis, tem intended to facilitate accurate dosing”, Proc. ± 1.4 % of this amount was found in the sinuses.16 BL (2004), “Next Generation Pharmaceutical Respir. Drug Delivery Europe, 341-344. Compared with nasal sprays, nasal retention Impactor: a new impactor for pharmaceutical was prolonged by about four-fold with the Vibrent. inhaler testing”, J. Aerosol Med., 17 (4), 335-343. 15. Hahn, M; Tservistas, M; Hetzer, U; Seidler, A; Our data provide evidence that ventilation and Grieblinger, E; Knoch, M (2009), “In-vitro assess- topical drug delivery to the posterior nose and 7. Schuschnig, U; Hug, M; Klopfer, E; Knoch, ment of a novel nebuliser for mechanically ventilated osteomeatal area, including paranasal sinuses, is M; Keller, M (2007), “The next Generation patients based on the eFlow technology”, J. Aerosol possible with the Vibrent offering new therapeutic Impactor: Effects of environmental conditions Med. Pulm. Drug Delivery 22 (2), 187-188. perspectives for CRS and CF sufferers.16 and impactor temperature on particle size measurements of aqueous aerosols”, Proc. Respir. 16. Moeller, W; Schuschnig, U; Khadem Saba, SUMMARY AND CONCLUSION Drug Delivery Europe, 311-316. G; Meyer, G; Junge-Huelsing, B; Keller, M; Haeussinger, K (2010), “Pulsating aerosols PARI Pharma has an outstanding track 8. Keller, M; Schuschnig, U; Hug, M; Bucholski, for drug delivery to the sinuses in healthy vol- record and strong expertise in the development A (2007) “Importance of the Inhaler System and unteers”, Otolaryngol. Head and Neck Surgery and manufacture of nebulisers including large- Relative Humidity on the Fine Particle Dose 142, 382-388.

OOINDPINDP MMarar 2010.indd2010.indd 1616 222/3/102/3/10 08:59:1108:59:11 OOINDPINDP MMarar 2010.indd2010.indd 1717 222/3/102/3/10 08:59:1108:59:11 OOINDPINDP MMarar 2010.indd2010.indd 1818 222/3/102/3/10 08:59:1108:59:11 691591-A

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OOINDPINDP MMarar 2010.indd2010.indd 1919 222/3/102/3/10 08:59:1408:59:14 AUTOMATED ACTUATIONS FACILITATING COMPENDIAL TESTING OF NASAL SPRAY AND METERED DOSE INHALER PRODUCTS

For metered dose inhalers and nasal spray pumps, the testing of various product characteristics including plume geometry, spray pattern, dose-weight and dose content uniformity, is facilitated by automated actuators. In this article, Henrik G. Krarup, Vice-President, Business Development at InnovaSystems, Inc, describes how these actuators fit in at the heart of the product testing process and how this process is benefiting from innovative actuator designs.

The US FDA has formulated guidances for components and pressure-resistant polymers the pharmaceutical industry dealing with the for tubing. various aspects of submitting data on NDAs To supply the necessary equivalent force and ANDAs for nasal aerosols, nasal sprays and of a strong human hand (around 80N) only 90 metered dose inhalers (MDIs).1-3 These drug PSI (approximately 6kg/cm2) is required from delivery systems are designed for patients to the compressed gas source. The actual amount administer by hand actuation and the guidance of gas needed is small and many labs run their documents deal with the various characterisation actuators from tanks enjoying the flexibility of aspects of the sprayed or aerosolised products. switching between compressed air and nitrogen. For in vitro testing it is recommended to This principle of operation provides a simple use automated actuations to minimise potential solution with a minimal amount of moving parts operator bias. For delivery systems that entirely and need for maintenance. rely on the force exerted by the human hand, the The development of the pneumatic actuators natural variation of the magnitude of this source has advanced from the stand-alone type NSP to of force has a direct bearing on the variability the software controlled eNSP and the popular of droplet size distributions and spray patterns. MightyRunt. All the pneumatic actuators (see Under these conditions automated actuations figure 1) are controlled by specifying the help to minimise the variability of data and amount of equivalent force that is needed for thus facilitate product comparisons. Beyond the actuation. During a time span of 10 years pure statistical validation, automated actuators the actuators expanded their role and use also save pharmaceutical employees long-term from primarily delivering products for shot joint damage from repetitive movements during weights and dose content uniformity (DCU) Henrik G. Krarup testing of these products. to spray delivery for laser-based droplet size Vice-President of Business distribution determinations. As a consequence Development ACTUATORS the MightyRunt actuator was designed with a T: +1 828 863 2506 low positioned actuator plate which allowed E: [email protected] Since 1989, InnovaSystems has developed positioning of the nasal spray nozzle tip below automated actuators. From an engineering the laser beam of the early laser diffraction InnovaSystems, Inc perspective the actuator converts one form instruments. 1245 N. Church Street, Unit 6 Moorestown of energy (compressed air or electricity) As laboratrory space became a priced NJ 08057 into mechanical force signified by movement commodity in pharmaceutical labs it often United States of the actuator plate on which the drug happened that the actuator would not have access delivery system rests. Previously, compressed to compressed air within its intended area of T: +1 856 722 0410 air was considered an integral part of any lab operation. Consequently a customer-driven need F: +1856 722-0042 environment, which was taken advantage of spurred the development of actuators operating E: [email protected] in the design of the early actuators. Control on principles of electrical motors. However, of compressed air has reached a mature state this principle of operation is slightly more www.innovasystemsinc.com providing well functioning electronic valve complicated than the pneumatic principle.

OOINDPINDP MMarar 2010.indd2010.indd 2020 222/3/102/3/10 08:59:2008:59:20 MDI-AS actuator. Product agitation via MightyRunt NSP actuator MDI FD-10 Repeated rotational or vertical shake followed by stepper motor at programmable angles actuation of 10 MDI products Figure 1: Pneumatic Test Equipment Electrical motors are well controlled but require maintenance demanding. On the application any need for supervision. Waste material is an addition of threaded spindles or lead screws side, the linear motor offers operation in handled through a vacuum system to a filter. to provide translational motion. By observing either a force-based or velocity-based mode. Preparation of samples for DCU may be Maxwell’s modification of Faraday’s law of This provides the advantage of reproducing added as a feature to the DW station (figure 7). induction (see figure 2) we can appreciate that performance of the earlier pneumatic and A further gantry system now handles capped by changing the magnetic flux, an electromotive rotational-electrical actuators from one single force is induced. The electrical motor is thus actuator unit. d realised by placing an electromagnet between two B permanent magnets. When the electromagnet is DETERMINING ACTUATION dt charged by the electric source, the generated flux PARAMETERS where induces the electromotive force needed to turn the electromagnet around its axle, which becomes The FDA guidance documentation referred is the electromotive force

the rotor. The stationary part (in this case the to previously recommends that the parameters d B is the change in the magnetic ﬂux permanent magnets) are referred to as the stator. chosen for the operation of the actuators should As mentioned above, a further addition of a make the instruments perform the pump actuations lead screw, as used in the familiar micrometer in manners similar to those in which a trained caliper, will allow the transformation from patient would. To this purpose InnovaSystems N SOUTH rotational to translational motion. This has has developed Hand Actuation Monitors Commutator

become the principle of operation of the (HAMs; see figure 5a) that allow operators to Brushes NORTH electrical VA actuator (see figure 3), which is characterise hand actuations for determining the Axle controlled by specifying the velocity required range of forces and velocities. Figure 5b shows 4 Armature during the actuation. results obtained from a HAM. These devices battery To InnovaSystems’ dedication to providing significantly reduce the work associated with superior automated test solutions has taken justifying the chosen actuator parameters. FIELD MAGNET the electrical actuator to the next level – linear Figure 2: Maxwell’s modification of motor actuators. COMPENDIAL TESTS Faraday’s Law of Induction, and the Linear motors that originally were known principle of a rotational motor from magnetic levitated train and plotter The actuator thus becomes the cornerstone of applications were previously highly priced, but the test station that deals with the compendial test have now matured to a lower price level such requirements for priming/re-priming, dose weight, that they are serious competitors to traditional content uniformity preparation, spray pattern and rotational motors. The primary motion of plume geometry. The stations are designed to be the linear motor is translational which for scalable to accommodate the different capacity actuators offers a very desirable advantage over needs from R&D to QC environments. converting the movement of a rotational motor. Single-product dose-weight testing may be By unfolding the stator of the rotational motor performed on a Pump Actuation Weight Station the induced force becomes linear rather than a (PAWS; see figure 6). As the pump is actuated torque (or rotation). Pulsing the electromagnets the dose weight is automatically recorded in (see figure 4) allows the central coils to move in the software. a highly controllable linear manner. Multiple-product dose-weight testing may be This operating principle by-passes the performed on a NSP-DW or MDI-DW station. inherent friction-wear issue of the rotational A gantry system sequentially moves 20 samples motor such that the actuator in which it is used between the test rack and the actuator. Actuation Figure 3. The Velocity Controlled becomes more efficient, more accurate and less and dose weight registration happens without VA Actuator

OOINDPINDP MMarar 2010.indd2010.indd 2121 222/3/102/3/10 08:59:2008:59:20 a b

N S N S

S N S N

N S N S

S N S N

Figure 4: Configuration Figure 5: a) HAM with a load cell for electronic transfer of Hand Actuation Parameters to the actuator of a Linear Motor. software. b) Travel and Force Curves obtained with the HAM Device Centre coils perform a linear upwards or programming surface. The FD-10 instrument dose weight, preparation for dose content downwards motion was displayed previously together with the other uniformity, spray pattern and plume geometry. between electromag- pneumatic systems in figure 1. nets sequentially Plume geometry is not used in Quality REFERENCES switched on and off Control (QC) for release but can be a useful sample tubes and brings them to the actuator tool during product characterisation of both 1. 5383DFT: “Bioavailability and where the subsample is delivered to the test NSPs and MDIs. Spray pattern however is Bioequivalence Studies for Nasal Aerosols and tube. A predetermined amount of solvent is used routinely in QC for release. Traditionally Nasal Sprays for Local Action”. added to the subsample, which subsequently is these tests have been performed with impaction www.fda.gov/downloads/Drugs/ capped and agitated in its preparation for DCU. systems such as TLC plates and fast-speed GuidanceComplianceRegulatoryInformation/ Weights are documented from every step and all cameras. InnovaSystems has developed a Guidances/UCM070111.pdf data ported to an ASCII file which subsequently non-impaction laser-based system that allows may be streamed to the customers LIMS system. automated acquisition of digitised images of 2. 4234FNL: “Nasal Spray and Inhalation The return on investment (ROI) is remarkably the spray pattern and plume geometry of both Solution, Suspension, and Spray Drug Products high if a complete stability study is considered, NSPs and MDIs (figure 8). The software allows Chemistry, Manufacturing, and Controls involving 10,000 tests including waste sprays, the operator to specify an electronic shutter and Documentation”. www.fda.gov/downloads/Drugs/ dose weights, DCU, multiple strengths, multiple threshold level such that the perimeter of the GuidanceComplianceRegulatoryInformation/ lots and multiple pulls. true shape of the spray pattern includes a high Guidances/ucm070575.pdf The pneumatic actuation principle is applied proportion (inclusion ratio > 95%) of the total in the Fire Down 10 (FD-10) which allows pattern as recommended by the FDA. 3. 2180DFT: “Metered Dose Inhaler (MDI) and simultaneous testing of 10 MDI canisters at a Dry powder Inhaler (DPI) Drug Products”. time. This performance specifically relates to SUMMARY www.fda.gov/downloads/Drugs/ “DCU Through Container Life”. The canisters GuidanceComplianceRegulatoryInformation/ are first rotationally or vertically shaken, and InnovaSystems has a long tradition of Guidances/ucm070573.pdf then fired such that the canisters quickly and providing high-quality equipment for the testing efficiently can be DCU tested at initial fill % of drug delivery systems. The company takes 4. Doughty DV, Dalby RN (2007). “Determination and later at 50% full. The discharge is evacuated great pride in providing the most advanced of automated nasal actuator parameters based to a filter through a vacuum system. This is and reliable actuators that form the core of its on a twenty volunteer study”. Respiratory Drug a compact stand-alone system with a keypad scalable test systems for priming/re-priming, Delivery Europe 2007, 349-352.

Figure 6: Pump Actuation Figure 7: Fully automated system for Nasal Spray Figure 8: Aerosol Drug Spray Analyser for spray Weight Station for Dose Weight determination. In addition, sub- pattern and plume geometry of both MDIs automated dose weight samples are automatically prepared for Dose Content (shown here) and nasal spray pumps. They determination of individual Uniformity testing colorized inserts show plume geometry (left) nasal spray pumps and spray pattern (right) images

OOINDPINDP MMarar 2010.indd2010.indd 2222 222/3/102/3/10 08:59:2108:59:21 Innvova redone.indd 1 18/3/10 00:54:44 Complete automated test solutions for Metered Dose Inhalers and Nasal Spray Pumps

Actuations

Tail Off

Prime—Reprime

Dose Weight

Prep for DCU* Since 1989, InnovaSystems has been an industry leader providing a full suite of automated test stations. These automated stations improve data reproducibility, staff productivity, testing throughput, quality, and safety.

With a worldwide installed base of over 500 systems, in both quality control and research & development departments, InnovaSystems continues to provide specifi c, reliable solutions. Providing our customers with fl exible, affordable, high quality service and support programs is a key factor for our continuing success. Actuations for DSD** All our stations are designed to facilitate Spray Pattern customer commissioning by supporting 21 CFR Part 11 compliance. IQ/OQ documentation Plume Geometry simplifi es validation and implementation. Complete customer training, on-going support, and extended warranties provide worry free ownership.

InnovaSystems is committed to the continued success of our clients www.InnovaSystemsInc.com

USA Europe India InnovaSystems, Inc. LTB Associates Ltd AIMIL Ltd 1245 N. Church Street, Unit 6 56 High Street Naimex House A-8, Mohan Moorestown, New Jersey 08057 The Old Coach House Cooperative Industrial Estate Tel: (856) 722-0410 Harston, Cambridgeshire CB22 7PZ Mathura Road, New Delhi- 110044 * Dose Content Uniformity Fax: (856) 722-0042 Tel: +44 (0) 1223-872-802 Tel: +91 11 30810200 ** Droplet Size Distribution [email protected] [email protected] [email protected]

InnvovaOOINDPINDP MMar redone.inddar 2010.indd2010.ind d 1 2323 18/3/10222/3/102/3/10 00:54:4408:59:2208:59:22 COMPANY PROFILE - CATALENT PHARMA SOLUTIONS

Catalent holds more than 1,500 patents and patent applications in advanced drug delivery, biologics formulation, manufacturing and packaging. With experience in more than 100 countries, extensive knowledge of the pharmaceutical, biotechnology and consumer mar- Catalent Pharma Solutions is a leading pro- kets, and a global facility network that spans vider of advanced dose form and packaging five continents, Catalent is well positioned to technologies as well as development, manu- serve you, wherever you do business. facturing and packaging services for pharmaceutical, biotechnology and consumer SERVICES OFFERED: health companies. Catalent applies its local market expertise and technical creativity Development to advance treatments, change markets and Catalent offers a full range of product devel- enhance patient outcomes. opment services, such as preclinical support, API development, analytical services, clinical Catalent’s proprietary drug delivery and manufacturing and packaging, and global reg- packaging technologies enable customers ulatory and clinical support services. We have Liqui-Gels® capsules and Vegicaps® Soft to achieve their desired clinical and market expertise in inhalation development, and can capsules; Zydis® fast dissolve dosage form; outcomes, and are used in many well-known offer innovative biologic cell-line development oral controlled release technologies; and products. The Company provides innova- using our proprietary GPEx® technology. inhaled dose forms. tive product development, superior quality, advanced manufacturing and skilled techni- Drug Delivery Manufacturing cal service to support its customers’ devel- We are a world leader in drug delivery sys- We provide manufacturing for nearly every opment and product needs. tems. Our technologies include: softgels, major dose form on the market today. Along with our proprietary dose forms, we also manufacture traditional oral, sterile and inhaled dose forms. We also produce biologics for preclinical and clinical studies.

Packaging Catalent is the largest provider of packaging services to the pharmaceutical industry. Globally positioned, our packaging services include clinical supply services, commercial packaging for all dose forms and the supply of printed components. We specialise in new product launch support and are the recognized leader in the packaging of biotechnology products, and the design and development of innovative compliance packaging, such as RxBarrier+™ for oral solid medications, and novel unit-dose formats like DelPouch® for liquids and creams.

Catalent Pharma Solutions 14 Schoolhouse Road Somerset NJ 08873

T: +1 866 720 3148 E: [email protected]

www.catalent.com

OOINDPINDP MMarar 2010.indd2010.indd 2424 222/3/102/3/10 08:59:2208:59:22 1519 Ferdinand Magellan set out to circumnavigate the globe… 1991 Magellan Labs was founded to serve the globe’s need for contract analytical services… Magellan Labs is later transitioned to Catalent Pharma Solutions. Discover how we can put our heritage to work for you.

From rapid testing of early candidates, regulatory With world-class technology, global presence, and submission and commercial support, Catalent has a team of expert scientists that is unmatched in the the CMC development expertise and integrated industry, we can accelerate your speed to market. capabilities to bring your pharmaceutical products Catalent offers a full range of CMC development to to life – faster, more cost-effectively, and with support the successful development and CMC filing unparalleled service and support. of your products, including:

Mammalian Cell Line Development • Formulation Development • Analytical R&D Bioassay/Biosafety • Structural Characterization • Stability & Testing Microbiology • Compendial Analysis • Clinical Supply

OOINDPINDP MMarar 2010.indd2010.indd 2525 222/3/102/3/10 08:59:2508:59:25 ENVISION LASER-BASED IMAGING SYSTEM: FULLY CHARACTERISES NASALASAL- AND DRY POWDER-BASED SYSTEMS

The EnVision system is a fast and effective platform for benchmarking devices too assesassesss the impact of changes in design and how different ingredients are handled by differentdifferent device platforms. It provides important insight into the fluidisation and behaviourehaviour of powder inside dry powder devices. Here, Dr Séamus Murphy, Manager, Imaging Division, and Dr Tim Stephens, Imaging Systems Engineer, both of Oxford Lasers,rs, review current technology and application techniques and outline how advances in technologynology are utilised to characterise nasal sprays and dry-powder inhalers (DPIs).

Oxford Lasers has supplied groundbreaking the EnVision system can be positionedositioned in imaging technology to the pharmaceutical any lab. At the heart of the sysystemstem are a and medical devices sector for over a decade, light source, high-speed cameraa and a suite ooff providing scientists and engineers with insight advanced software. into device behaviour. The light source is an Oxford Lasers FireFly For nasal sprays the the Oxford Lasers pulsed diode laser system, designed for high- Figure 1: EnVision system with Class EnVision system provides information on three speed imaging applications. Operating at a I laser safety enclosure areas of interest: the effect of changing operating wavelength of 808nm, the laser can provide very conditions (for example, pump actuation force or short pulses down to 500 nanoseconds in duration. velocity); how solution type affects performance; Because the light source is pulsed, the captured and the velocity profile across a typical nasal images are free from motion blur and are suitable spray. We will also look at the complex flow inside for use in more advanced analysis techniques. the nasal cavity and how imaging techniques can The laser can operate at up to 10,000Hz in assess the flow regimes through nasal passages. continuous mode but for short periods can run For DPIs the EnVision system gives images in burst mode giving an equivalent frequency of the fluidisation process and flow behaviour of 1,000,000Hz. The internally adjustable optics inside the device. Combined with advanced allow the user to configure the light source analytical techniques it is possible to collect around different devices, and provide multiple 2 information on the flow velocity, particle size modes of illumination (for example, a light sheet Dr Séamus D. Murphy and particle velocity. for visualising a plane through a spray plume). Manager, Imaging Division EnVision systems (see figure 1) are designed The high-frequency camera has a CMOS T: +44 1235 812255 to capture sequences of images from transient (complementary metal oxide semiconductor) F: +44 1235 810060 E: [email protected] events. The unique platform employs a safety sensor with large area pixels, giving optimum light enclosure, short-pulsed laser light source, high- sensitivity. The standard version can run at frame- frequency camera and image analysis software rates from 500Hz to 10,000Hz at full resolution. Dr Tim Stephens Imaging Systems Engineer to provide information on particle size, particle Higher frequency options give a frequency range E: [email protected] velocity, flow field vector analysis and general up to 1,250,000Hz with reduced resolution. These spray characterisation of spray pattern and plume astonishing frame-rates mean that drug delivery Oxford Lasers Ltd 1 geometry in line with US FDA guidelines. processes can be viewed in unprecedented detail. Unit 8 Moorbrook Park, Didcot IMAGING HARDWARE ANALYSIS TECHNIQUES Oxfordshire OX11 7HP United Kingdom By courtesy of its Class I laser-safe enclosure There are predominantly three types of image system, the EnVision system conforms fully to analysis used on nasal and DPI platforms, providing www.oxfordlasers.com all laser safety requirements. This means that a range of data, for the evaluation of devices;

OOINDPINDP MMarar 2010.indd2010.indd 2626 222/3/102/3/10 08:59:2508:59:25 Figure 2: a) Plume geometry and b) spray pattern images from EnVision QC system Figure 3: VisiSizer – particle size and par- with fully automated analysis ticle velocity analysis for droplets in flight with background illumination. Particles 1. General Characterisation of plume geometry to identify particles in the images. Once appear black on a bright background and spray pattern identified, the software determines the position This long-established technique uses a light of the particle in relation to the plane of Three recent examples demonstrate how sheet aligned either along the axis of the spray focus by comparing the edge-sharpness to the EnVision system has been used to assess a or orthogonal to it.3 The Oxford Lasers EnVision a predetermined calibration, and reports the nasal spray: Patternate software integrates a series of images correct particle size. Particle velocity can be Application 1 – Williams et al studied the of the spray, detects the boundary pattern or measured by tracking the particle movement influence of pump type, actuation operating geometry and reports either spray pattern or between two sequential images. conditions and type of solution on the aerosol plume geometry parameters. Figure 2 shows particle velocity.6 typical images of the spray pattern and plume 3. Flow Field Vector Analysis A high-speed sequence of backlit images geometry. This type of basic system is widely This technique provides detailed information of (see figure 3) of the device actuation event was used in the pharmaceutical industry to test the flow velocity in a plane within the flow during acquired, and particle size and particle velocity devices in accordance with FDA Guidlines. 1 an event by using a light sheet configuration information collected. similar to the general characterisation setup. The velocity of the droplets ranged between 2. Particle Size Characterisation To obtain vector information, two sequential 1.7 and 28.6m/s. For both nasal spray pump A and Image-based particle sizing was first developed images are compared using a cross-correlation pump B the average droplet velocity ranged from in the 1970s but did not become widespread until technique to measure the particle shift between 8.4 and 12.8m/s. The advanced particle sizing tech- the 1990s when personal computers became them. The analysis software divides the images niques allowed the user to collect detailed informa- more affordable and readily available.4 For into small integration regions and determines tion on size and velocity of the drops in flight to particle sizing a back-illumination technique is the change in pattern between a pair of adjacent make the necessary comparison (see figure 4). used, with the light source and camera directly images to report the vector information. Murphy Application 2 – Williams et al set out to opposite each other. The light from the laser provides more detailed information on image- look at the variation in the velocity profile at is transmitted through a diffuser arrangement, based techniques.2,5 multiple positions in the spray plume for a range lighting up the area behind the particles. In of nasal spray pumps.7 this way, the camera captures images of the ANALYSIS OF NASAL DEVICES The Evaluation was carried out using an silhouettes of the particles as they move through EnVision system using a light-sheet configura- the measurement zone. EnVision provides a unique platform to tion. Oxford Lasers’ VidPIV software was used To determine the size, Oxford Lasers complete an extensive range of characterisations to analysis the pairs of images, using adaptive VisiSizer analysis software measures the shape, from straightforward high-speed imaging to the cross-correlation techniques, to determine veloc- area and edge sharpness of the silhouette more advanced techniques described above. ity vector information.

Figure 4: Comparison of two different nasal Figure 5: Sample image of flow-field vector Figure 6: Fracturing behaviour pumps with three different viscosity solutions in information collected inside the nasal cavity of dry powder, showing powder each. Results show that velocity of spray is not bed break-up and fluidisation affected by solution viscosity. process

OOINDPINDP MMarar 2010.indd2010.indd 2727 222/3/102/3/10 08:59:2708:59:27 REFERENCES

1. “Guidance for Industry, Nasal Spray and Inhalation solution, suspension and spray drug products”, CMC documents, Dept of Health and Human Services, FDA. CDER, July 2002.

2. S. Murphy, T. Stephens, “Analysis and Measurement of Drug Delivery Devices Using Figure 7: Images showing the movement of powder through a dry-powder device Alternative Imaging Techniques”, Work Shop Session RDD Europe 2009 Lisbon. The average aerosol velocity ranged ANALYSIS OF A DPI from 6.8 to 14.6m/s at various positions 3. G. S. Settles, “A Flow Visualisation Study of through the spray. The EnVision platform EnVision systems, with their combination Airless Spray Painting”, ILASS – Americas 97, is a unique platform for the characterisation of high-speed imaging and advanced analysis May 18-21, 1997, Ottawa, Canada. of pharmaceutical nasal spray velocity techniques are proving invaluable tools in the and can support efforts to meet regulatory understanding of DPIs. 4. A. Whybrew, T. R. Nicholls, “Diode Lasers requirements. When used in conjunction with Extensive studies by R Price and J Shur – A Cost Effective Tool for Simultaneous other measurement techniques it can provide have investigated the effect of different powder Visualisation, Sizing”, and “Velocity an understanding of particle transportation and formulations on system performance by Measurements of Sprays”, ILASS – Europe deposition within the nasal cavity.7 examining fluidisation and deaggregation of the 2009, Toulouse 5 – 7 July 1999. Application 3 – Doorly et al completed powder. 9-11 In figure 6 the EnVision high-speed extensive studies on the flow regimes through imaging system was used to acquire images of 5. S. Murphy, “Visualising Particles in nasal passages.8 the fluidisation process at 8,000Hz to show how Extreme Cold Gas Dynamic Spraying”, The study focused on the complex geometry the powder bed fractures. Powder Flow 2009 London http://www.formu- of the nasal passage and how it controls the lation.org.uk/conference-abstracts.html. airflow in various physiological functions. DIRECT EVALUATION OF THE FLOW Since the nasal passageway has complex OF POWDER INSIDE A DPI 6. G. Williams, J. C. Gilles, S. Murphy and G. morphology and is inaccessible, detailed in Veal, “Evaluation of Aerosol Particle Velocity vivo measurement was not possible. As a result Advanced imaging and illumination in Pharmaceutical Nasal Spray Pumps”, AAPS the only way to investigate the problem, was techniques make it possible to see how the National meeting 2007. using computational simulation and in vitro powder is fluidised, entrained and expelled experiments. from a DPI system. Figure 7 shows how a back- 7. G. Williams, J. C. Gilles, S. Murphy, A replica model of a nasal cavity was pro- illumination technique can reveal initiation of “Velocity Profiling of Sprays From duced and derived from in vivo scans. General the process. As powder is drawn from the Pharmaceutical Nasal Spray Pumps”, RDD high-speed imaging techniques and flow-field system the images show how the powder bed is Europe 2009 Lisbon. vector analysis were used to investigate the flow broken up and how fluidisation and entrainment through the nasal passage. of the powder in the airflow occurs. 8. D. J. Doorly, D. J. Taylor, P. Franke and The flow field vector technique with con- With light-sheet illumination, flow-field R.C. Schrouter, “Experimental Investigation of trolled artificial seeding was shown to provide vector analysis can be applied to determine Nasal Airflow”, Pro. IMechE Vol. 222 Part H: quantitative measurement of the flow velocity the flow-velocity profile inside the dry-powder J. Engineering in Medicine P439 – 453 2008. (figure 5), with peak velocities of 3 m/s. system. Figure 8 illustrates how the flow rotates inside the chamber before being drawn out 9. R. Price. “The Fluidisation behaviour of through the outlet into the patient pharmaceutical powders and their influence on particle deaggregation”, Powder Flow 2009 – SUMMARY London.

Advanced image-based systems such as 10. J. Shur, H. Harris, M. D. Jones, J. S. the EnVision system are providing unique Kaerger, and R. Price, “The Role of Fines information to aid the understanding and in the Modification of the Fluidization and development of both nasal and dry-powder Dispersion Mechanism Within Dry Powder devices. The combination of short pulse- Inhaler Formulations”, Pharmaceutical duration laser light sources and high-quality Research. images allow users to access more power- ful analytical techniques not traditionally 11. J. Shur, P. Rogueda and R. Price, used within the pharmaceutical industry. “Relationship Between Powder Fluidisation Figure 8: Flow-field map of the flow inside a dry-powder device and as the Furthermore, these techniques are a useful and Performance of Dry Powder Inhaler powder is ejected. Velocity range in this platform to support efforts to meet regulatory Formulations”, Drug Delivery to the Lungs application 0.0 to 2.8m/s. requirements. 7 2009

OOINDPINDP MMarar 2010.indd2010.indd 2828 222/3/102/3/10 08:59:2908:59:29 Oxford lasers ad.indd 1 16/3/10 11:46:05 Do You Study the Behaviour of Inhaled Drug Delivery Devices?

Oxford Lasers can help you to collect information about Dry Powder Inhalers, MDI and Nasal Sprays Oxford Lasers has a wide range of measurement systems

Spray Pattern/Plume Geometry

Customised Measure FDA required spray parameters Solutions Develop devices/perform QC on the same system • Systems tailored Full 21 CFR pt. 11 compliance to individual needs • Advanced integrated platform • Class I laser safe enclosure options Particle Sizing • Particle Size & VVelocity • Direction & SShapeha • Validate CFD mmodels • SSolids,olids, Liquids and BBubblesubbles

Flow Field Vector Analysis • Study regional fl ow behaviour • Quantify fl ow vectors Contact an • See time-resolved fl ow development Oxford Lasers representative for additional information

Unit 8, Moorbrook Park, Didcot, Oxon, OX11 7HP, UK Unit D201, 2 Shaker Road, Shirley, MA 01464, USA Tel: +44 (0) 1235 812255 Tel: (978) 425 0755 Email: [email protected] www.OXFORDLASERS.com

OOINDPOxfordINDP lasersMMarar 2010.indd2 0ad.indd10.indd 1 2929 222/3/1016/3/102/3/10 08:59:29011:46:058:59:29 PRODUCT PROFILE – BÜCHI’S NANO SPRAY DRYER: A WORLD NOVELTY IN LABORATORY SCALE

EXPERIENCE SUBMICRON SPRAY DRYING

Büchi’s latest instrument generation – the Nano Spray Dryer B-90 – revolutionises spray drying with an innovative technology for particle creation down to the submicron and even nanometre range from minimal sample quantities at highest yield.

Spray drying becomes increasingly important in drug development, formulation and particle design as a gentle, easy-to-control, continuous and scalable process to convert liquid formulations directly dry powders.

The Nano Spray Dryer B-90 is especially Büchi‘s Nano Spray Dryer B-90 designed for the early stages of product development. The modular glass assembly enables A unique heater technology based on porous Since 1979, BÜCHI Labortechnik AG offers a visible spray process and a quick and gentle metal foam provides a laminar gas flow in the the Mini Spray Dryers B-190, B-191 and drying of various applications in small scale, drying section. Optimal energy input guaran- B-290 and is the worldwide market leader in ideal for feasibility studies in R&D laborato- tees fast heat-up times up to 120°C for very laboratory scale spray dryers. Over 2900 units ries to dry only a few millilitres of substance. gentle drying of heat-sensitive materials. have been installed at universities, R&D cen- tres and powder specialists around the world. The Nano Spray Dryer B-90 meets the The fine spray dried particles are separated requirements of the pharma, biotech, medi- by an electrostatic particle collector, a novel Visit our free on-line Spray Dryer Application cal, food ingredient, chemical and advanced technology in laboratory scale. The elec- Database at www.buchi.com and be inspired material industry as well as nanotechnology. trostatic particle collector offers excellent by the wide variety of applications! New application trends focus on effective particle recovery rates for samples in the formulation of complex pharmaceuticals milligram range. It enables an easy collec- and nanomaterials for novel drug delivery tion of small powder amounts of high value systems, like inhalable powders. Typical materials at high yields. applications are spray drying of aqueous or solvent based solutions, nano-emulsions, The integrated LCD display ensures easy nanoparticle suspensions, structural transfor- process control. The PC software provides mations or nano-encapsulations. comprehensive data acquisition, storage and export capabilities. The transparency The droplet generation is based on a piezo- from spray head to particle collector due to electric driven actuator, vibrating a thin, the glass assembly and the very short set- Dr Cordin Arpagaus perforated membrane in a small spray cap. up times enable an easy cleaning and even Product Manager T: +41 71 394 65 08 The membrane features an array of micron- sterilisation. F: +41 71 394 63 11 sized holes. The actuator is driven at ultra- E: [email protected] sonic frequency, causing the membrane • Produce finest particles of 300nm to 5μm to vibrate, ejecting every second millions size with very narrow size distribution BÜCHI Labortechnik AG of precisely sized droplets with very nar- • Dry samples in the milligram range Meierseggstrasse 40 row droplet distribution. Different spray • Profit from minimal product loss due to 9230 Flawil caps with 4.0, 5.5 and 7.0μm hole sizes are uniquely high yields up to 90% Switzerland available to achieve a precise droplet size • Save process time thanks to quick assem- www.buchi.com between 8 and 21μm. bly, easy cleaning and fast product change

OOINDPINDP MMarar 2010.indd2010.indd 3030 222/3/102/3/10 08:59:3008:59:30 Spray Drying R&D Solutions

Buchi — your experienced partner in laboratory scale spray drying

The Mini Spray Dryer B-290 and Nano Spray Dryer B-90 are the perfect solution for:

s spray drying defined particle sizes from 300 nm to 30 μm s gentle drying of aqueous and organic solvents or blends s quick drying of small volumes from 1 ml with 90% recovery up to 1 l/h capacity s drying all kind of liquid samples (solutions, emulsions, suspensions) s encapsulation of any active ingredient even by spray chilling

We can custom configure a spray drying suite of instruments for your specific needs. Visit our free online Spray Drying Application Database on www.buchi.com

BÜCHI Labortechnik AG 9230 Flawil / Switzerland T +41 71 394 63 63 F +41 71 394 64 64

www.buchi.com Quality in your hands

OOINDPINDP MMarar 2010.indd2010.indd 3131 222/3/102/3/10 08:59:3108:59:31 OOINDPINDP MMarar 2010.indd2010.indd 3232 222/3/102/3/10 08:59:3108:59:31