Aspects of Particle Science and Regulation in Pharmaceutical Inhalation Drug Products

Lee M. Nagao,* Svetlana Lyapustina, Melinda K. Munos, and Mary Devlin Capizzi
Pharmaceutical Practice Group, Gardner Carton and Douglas, LLP, 1301 K Street, NW, Suite 900, East Tower, Washington, D.C. 20005 Received May 20, 2005

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2005 VOL. 5, NO. 6 2261-2267

ABSTRACT: Pharmaceutical orally inhaled drug products such as metered dose inhalers (MDIs) and dry powder inhalers (DPIs) are used by millions of individuals worldwide to treat symptoms of asthma and chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema). Other applications of these products are being developed including inhalation delivery of insulin and medication to treat pain and the symptoms of cystic fibrosis. Analysis and control of particulate matter are important aspects of the development of these drug products. This includes the development and control of particles of drugs delivered to the patient and the characterization and control of foreign particles that may contaminate the final product. The chemistry and manufacture of these products historically have been strictly regulated by the United States Food and Drug Administration (FDA), with many challenging regulatory requirements applied to analysis and control of particles. This paper provides an overview of some of the main areas of particle analysis in inhalation drug products and the current regulatory challenges pertinent to these areas. Introduction Pharmaceutical inhalation drug products include the general categories of metered dose inhalers (MDIs), dry powder inhalers (DPIs), and products for nebulization. These products are used widely to treat the symptoms of asthma and chronic obstructive pulmonary disease (COPD). Such products may deliver any one or a combination of active pharmaceutical ingredients such as 2-adrenergic agonists, corticosteroids, cromolyn sodium, and muscarinic cholinoceptor inhibitors.1 Other inhalation drug products have been researched to treat symptoms of cystic fibrosis and lung complications due to AIDS.2,3 Inhalation products are also currently being developed to deliver drugs systemically (i.e., to the entire body), through the lungs, such as insulin for treatment of diabetes or pain-relief medication for prompt relief of cancer pain.4,5 This paper describes (i) the role of particles in inhalation drug products, (ii) two major areas of particle analysis in the development of inhalation drug products, PSD analysis and control of foreign particles, and (iii) regulatory challenges related to these areas of particle analysis. In general, inhalation drug products work by delivering an aerosol,6 consisting mainly of the active ingredient and often an excipient carrier, to the lungs of the patient. All these products consist of drug formulation delivered via a device. These products come in a great variety of designs created to effectively deliver a defined dose to the patient. For example, in MDIs and DPIs, drug formulation may be contained in a reservoir (e.g., metal or plastic canister) or in premetered blisters or capsules that are loaded into a delivery device. For reservoir products, specific amounts of drug formulation
Dedicated to Professor J. Michael McBride on the occasion of his 65th birthday. * To whom correspondence should be addressed. Phone: 202-2305165. E-mail: lnagao@gcd.com.

are measured into a metering chamber and released by an actuator. In all MDIs and DPIs, the patient inhales the formulation through a mouthpiece. For MDIs, drug formulation may be solutions or suspensions of active drug in an organic solvent, or propellant, such as chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA). CFCs for use in these products are being phased-out under the requirements of the Montreal Protocol. The CFCs and HFAs used in MDIs are liquefied under pressure while contained within the inhaler. However, once released into the ambient environment, these excipients transition to the gas phase, propelling forth an aerosol of drug particles at high velocity. The patient must time his/her inhalation with release of the aerosol to promote effective delivery to the lungs. For products containing insulin, the solvent may be water. MDI formulations may also contain cosolvents, such as ethanol, and surfactants such as lecithin. In DPIs, the active drug is often combined with a solid excipient carrier, usually lactose. This dry powder combination of drug and carrier is inhaled by the patient. Unlike in MDIs, the powder is typically delivered through the force of the patients own inhalation. Some newer products are being developed that contain electronics that control or disperse the dose or assist the patient in coordinating his/her inhalation with the release of the dose from the product.7 Products for nebulization are usually solutions or suspensions contained in ampules. These are placed in a device called a nebulizer, which aerosolizes the solution or suspension for inhalation by the patient. Drug particles in inhalation products may be crystalline or amorphous, depending on the proprietary formulations. Powder excipients such as lactose, in DPIs, are often crystalline. Because of the particulate nature of the dose in powders and suspensions, which constitute the majority of inhaled products, the characteristics of active drug particles and excipients in the formulation

10.1021/cg050224z CCC: $30.25 2005 American Chemical Society Published on Web 10/12/2005

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are an important aspect of the quality, safety, and efficacy of inhalation drug products. Furthermore, foreign particles (particulate matter that is not intended to be part of the drug formulation), which may contaminate the product, must also be carefully controlled, and to the extent possible, characterized by the product manufacturer. Important characteristics of the drug particle are size and shape. Manufacturers assess the particle size distribution (PSD) of the emitted aerosol to determine the specific distribution of drug particles in different size ranges. For foreign particles, size, shape, identity, and amount are all important. In most cases, inhalation drug products will deliver formulation directly to a diseased organ for treatment of chronic medical conditions (e.g., to diseased lung in the case of asthma or COPD) several times a day over many years. Consequently, the United States Food and Drug Administration (FDA) has imposed extensive regulation and controls on these products especially in the areas of chemistry and manufacturing, which includes PSD analysis and control of foreign particles.8,9 Currently, there is much discussion among FDA and manufacturers on these issues, with industry seeking clearer science and experience-based regulatory guidance in these areas. Role of Particles in Orally Inhaled Drug Products The airway passages important to delivery of inhalation drug products are the conducting airways, which include the trachea, bronchi, and bronchioles, and the respiratory airways, which include the respiratory bronchioles and the alveoli.10 Drug particles in the aerosols emitted by orally inhaled drug products must travel through the patients mouth and throat and into the conducting and respiratory airways. As an example, common compounds used in drug formulations to treat asthma include 2-adrenergic agonists. These agonists work by interacting with 2-receptors, promoting smooth muscle relaxation leading to bronchodilation and less restricted airflow through affected regions. Inhalation drugs containing these agonists attempt to target areas of the lung where 2-receptors may be found, such as in the smooth muscle of the bronchi and bronchioli.1 Regional deposition of particles in the lungs is a complex process and is difficult to predict and achieve. It is dependent on many factors relating to both patient breathing behavior and physical and chemical properties of the particles. Factors such as patient breathing patterns,11 patient coordination of dose actuation and inhalation,12 time that the drug spends in the airways (breathholding),13 particle hygroscopicity,14 and particle shape15 influence the effective deposition of particles in the various airway regions. In addition to these important factors, particle size has been shown to be a determinant of particle deposition into specific airway regions and the key physical characteristic determining particle deposition in the lungs.16 Particle size for inhalation drug delivery is described primarily by the aerodynamic diameter, which is the diameter of a sphere of unit density having the same settling velocity as the particle in question. A particle reaches its settling velocity when the drag force of air acting on the particles is equivalent to the force of

gravity on the particle, with the particle therefore achieving a constant velocity. The settling velocity is proportional to gravity and the particle density.16 Particles with equivalent aerodynamic diameters will have equivalent aerodynamic properties regardless of their size, shape, and density. The aerodynamic diameter, da, is defined by the particle volume equivalent diameter, dv, the particle density, Fp, a reference density taken as unit density (g/mL), F0, and a dynamic shape factor, , which provides a correction for nonspherical particles:

da ) dv

FpCp F0Cae

The Cunningham slip correction factors, Cp and Cae, become important when the particle is less than 1 m. For these particles, the relative velocity of the gas at the surface of the particle sphere is nonzero, and the particle sizes are close to the mean free path of the surrounding gas. The slip correction factors can be calculated from the expression:

Cp/ae ) 1 +

dp/ae

2.514 + 0.800 exp -0.55

dp/ae

])

where is the mean free path in the support gas. Cp and Cae are close to unity when dp, the diameter of the particle, is 1 m.17 Studies with stable monodisperse aerosols have shown that, in general, aerosol particles with aerodynamic diameters greater than 10 m tend to deposit in the mouth and throat, particles between 5 and 10 m tend to deposit in the trachea and bronchial regions, particles of approximately 3 m can deposit in the alveoli (although these will also deposit in mouth/throat and tracheobronchial regions), and submicron particles will tend to be exhaled (with the exception of ultrafine, i.e., nanomicron-sized particles, which can remain in the lung).15 It is important to note, however, that the aerosols emitted by inhalation products are polydisperse (i.e., consist of particles having a wide range of sizes) rather than monodisperse. Sometimes these polydisperse aerosols may exhibit a log-normal distribution. In this case, they may be described in terms of their mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD), which describes the variance in particle sizes.18 The size of aerosol particles may change after generation of the aerosol due to the combination of drug particles with excipients or other particles, or due to evaporation of the propellant or solvent.15 Typically not much more than 20% of the dose will be delivered to the conducting and respiratory airways, with these particles depositing throughout the airways.19 Deposition in the peripheral airways tends to occur for particles below about 5 microns.20 Particles depositing in the upper airways, or tracheal and bronchial regions, are usually cleared from these regions via mucociliary clearance over the course of several hours.15,19 Much of the dose, especially the larger particles, will deposit in the mouth and throat and will be swallowed. Manufacturers aim to reduce the variability of particle sizes within the emitted aerosol, attempting to limit particle

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sizes to the range of about 1-5 microns, to encourage deposition within the airways and discourage deposition in the mouth or back of the throat. Habit and morphology of drug particles may also contribute to regional deposition in the airways. Some evidence suggests that long needlelike particle or crystal habits may deposit more effectively into the deep lung such as the alveolar regions, and control of crystal growth to produce habits of this type for specific drug actives for inhalation has been performed.15,21 On the other hand, relatively spherical drug particles are often preferred for process reasons, as these impart better particle flow. Other examples of particle engineering include production of low density, porous spheres of drug, which reduce the median aerodynamic size of particles, can minimize particle flocculation in suspensions, and may potentially improve dose uniformity.22 In DPIs, active drug particles can be mixed with particles of a solid excipient carrier, usually lactose, which may have diameters of several tens of microns. In these products, the drug particles adhere to the surfaces of the lactose crystals. Ideally, the carrier will deposit primarily in the mouth and throat with the drug particles deaggregating from the carrier and depositing in the lower airways.23,24 Thus, adhesion properties of the active particles with the solid carrier are an important consideration in the development of effective dry powders for inhalation.25 Some studies have examined the use of atomic force microscopy to determine adhesion properties of the drug with specific faces of the lactose crystal.26 Drug-carrier interactions have also been studied using X-ray and spectroscopic techniques.27 Particle Size Distribution Analysis and Control of Foreign Particles in Orally Inhaled Drug Products Two areas of great interest to manufacturers of inhalation drug products and regulatory authorities are aerodynamic particle size distribution (APSD) analysis and control of foreign particles. Assessment of APSD and foreign particles are important in the development of high-quality, safe, and efficacious pharmaceuticals. Some industry groups have differed from FDA representatives on the use and interpretation of APSD results and have also sought clarified guidance on how best to control foreign particles in inhalation drug products. This paper first provides a general, brief description of APSD analysis via inertial impaction and approaches to foreign particles control and then describes some regulatory issues associated with these topics and ways in which FDA and industry are addressing these issues. Aerodynamic Particle Size Distribution Because of the importance of particle size in inhalation aerosol products, manufacturers developing such products would like to understand the range of particle aerodynamic diameters within the emitted aerosol. APSD analysis allows some understanding of this parameter. Furthermore, the FDA, in recent regulatory guidances for testing of orally inhaled drug products,8,9 has required that the mass balance of the resultant particle distribution be used to confirm the quality of

the inhalation product. This issue will be discussed later in this paper. APSD of the aerosol can be determined using a number of different techniques such as inertial impaction and laser diffraction. Manufacturers may use combinations of these techniques to assess their product. Instruments that exploit the physical phenomenon of inertial impaction to separate aerosol particles by size include cascade impactors and impingers.16,18 Inertial impaction via cascade impactors is discussed in further detail because it has a long history of use within the industry, and, as will be discussed later, aspects of its use have engendered regulatory controversy. Inertial impaction takes advantage of the aerodynamic behavior of particles in a gas flow.16,18,28 In general, aerosol is introduced to a gas flow traveling toward a stack of collection plates or other collection apparatus. Near each collection plate, gas flow will change direction traveling roughly parallel to the plate. Particles in the gas will lose inertia due to friction but then may proceed to follow the new flow direction. The time taken to do this is called the relaxation time and is proportional to the aerodynamic diameter and density of the particle. Small particles tend to exhibit a shorter relaxation time than the larger particles. The larger particles will therefore impact the collection plate, while smaller particles will continue in the new flow direction. Air flow velocity, distance of the collection plate to the gas opening or orifice, and collection plate diameter will contribute to the separation characteristics of the particles into distinct size or mass ranges at each impactor stage.16,28 Cascade impactors, originally developed to analyze particles in the environmental and occupational health arenas, are now commonly used in the pharmaceutical industry to assess PSD. A variety of different types are available, including the so-called next generation pharmaceutical impactor, which was developed by a consortium of pharmaceutical companies and impactor manufacturers.29-31 Cascade impactors consist of a sealed chamber containing a number of stages arranged in series, generally consisting of collection plates, and above each collection plate, a plate containing holes of specific diameter, through which the air and particles will flow. The impactor is connected to a vacuum pump, which induces the air flow. Particles collected from each collection plate may be analyzed, for instance, microscopically, chromatographically, and/or gravimetrically. Impactors usually also contain associated parts such as an induction port (to which the mouthpiece of the inhalation drug is attached) and sometimes a preseparator that removes large particles. Figure 1 shows a schematic cross-section of a cascade impactor and behavior of particles within the impactor.32 Cascade impactors are complex instruments that require trained analysts and present a number of challenges to the user.16,33 Sampling, for instance, is an important consideration for meaningful assessment of APSD for inhalation products. Induction ports attached to impactors may adopt a 90 degree angle curve to mimic patient mouth and throat geometry.18 Sampling of aerosols generated from an MDI or DPI, however, is highly dependent on analyst technique. Impactor calibration also presents a number of challenges as the

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Figure 1. Schematic cross-section of two consecutive stages of a cascade impactor demonstrating principle of size fractionation by inertial impaction. From one stage to the next, jet nozzles get smaller and air flow gets faster. Larger particles (with more inertia) leave the air stream and deposit on collection plates on earlier stages compared to the smaller particles.

calibration process is quite complex and must take into account the dimensions of the jet, the collection surface, and the airflow.34 The assessments that manufacturers may conduct on the PSD include mass of drug product on stages or on groupings of stages and the total mass balance. Mass balance with respect to PSD in cascade impactors may be defined as the sum of mass of active drug particles collected from the induction port, preseparator (if used), and all stages of the impactor.18,33 Particles are collected from each of these areas and chromatographically analyzed to determine total mass collected. In accordance with recent FDA guidances, results are to be compared with the drug content per dose as claimed on the label and must be within predefined limits of the label claim. The appropriate use of the PSD mass balance measurement, either as an indication of quality of the product or as a system suitability check, has been a subject of much debate between FDA and industry. The distribution of particle sizes is also used for comparisons of innovator and generic products, or of slightly modified products. The methods for comparing PSD profiles present a number of interesting challenges and are actively discussed by industry and regulators.35 Foreign Particles Another area in which analysis of particulate matter is of interest for inhalation drug products is the characterization and control of foreign particles. Foreign particles in pharmaceuticals are contaminants that are not part of the drug formulation and that may have been introduced to the formulation from the device components, bulk active, excipients, or drug product manufacturing process.36 Manufacturers characterize and enumerate foreign particles during product development. Product development occurs before and during the preparation of the new drug application, which is submitted to the FDA to obtain approval to market the product. Characterization may include identity, size, shape, and source of the

particle. Foreign particles may consist of, for example, fibers, metal particles, polymers, or talc. These particles can range in size from microns to several tens or hundreds of microns, and shape and density may vary widely. A number of different techniques exist to characterize and/or count foreign particles. These include light obscuration, optical microscopy, scanning electron microscopy with energy-dispersive X-ray, Raman microprobe, and FTIR microscopy. Each technique has limitations and advantages, and usually more than one is used in a development program.36 For example, light obscuration is useful for particle counting but not for characterization. In light obscuration, a sample dose is suspended in a liquid and exposed to a laser. Particles passing through the laser will scatter or absorb the light leading to a change in voltage in the detector. The amount of voltage needed to return the detector to its original voltage increases with increasing particle size. Particles can thus be counted in specific size ranges. On the other hand, Raman microprobe techniques, in which a Raman spectrometer is coupled with a microscope, allow identification of inorganic and organic materials but cannot detect and identify metals. The clinical and toxicological relevance of foreign particles in inhalation drug products is not well understood. Many studies have attempted to characterize the effects of inhaling potentially toxic particulate matter from the environment and the effect of size on the toxicity.37,38 However, due to the proprietary nature of foreign particle information for individual products, such as identity, amount, and size, there has not been, to date, an overall evaluation of the safety issues and clinical effects of such particles with respect to orally inhaled drug products. Pharmacopeial methods exist for analysis of foreign particles, particularly for parenteral dosage forms.39 There is currently very little FDA guidance available for orally inhaled and nasal drug products (OINDP) providing recommendations on issues such as when to conduct foreign particles testing in the pharmaceutical development process and what size ranges are important to consider. This has led to some confusion within industry regarding FDAs expectations for foreign particles testing and control, both in development and for batches of product to be released for sale. This is discussed further in the next section. Aspects of Regulatory Guidance Regarding Particles in Orally Inhaled Drug Products In 1998 and 1999, the FDA issued two draft documents providing regulatory guidance on chemistry and manufacturing controls for orally inhaled and nasal drug products: Draft Guidance for Industry, Chemistry Manufacturing and Controls Documentation for Metered Dose Inhalers and Dry Powder Inhalers, and Draft Guidance for Industry, Chemistry Manufacturing and Controls Documentation, Inhalation Solution, Suspension, and Spray, and Nasal Sprays.8,9 The inhalation solution, suspension and spray guidance was finalized in 2002. The MDI/DPI guidance is still in draft form. Guidance for industry issued by FDA provides information and recommendations on the tests and general approaches for manufacturers to consider when devel-

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oping a new drug application for submission to the agency. In principle, such guidance is based on research data and information compiled from industry, academic sources, and the agencys previous experiences. The guidance recommendations should also reflect the capabilities of current drug product technology. The issuance of the orally inhaled and nasal drug products guidances presented a significant advance as they provided for the first time, in documented form, the expectations of the FDA regarding tests that should be performed to assess product quality and regarding specifications for OINDP. When the draft guidances were issued, industry provided a great deal of comment to the agency, noting disagreement with approaches and acceptance criteria for some of the tests and seeking clarification for others.40 Particle Size Distribution Mass Balance As noted previously, PSD of aerosolized drugs can be measured using cascade impactors and is meant to provide information about the amount of active drug particles within specified size ranges. In addition, if the amount of drug on all impactor parts and accessories is summed, an additional measure can be obtaineds - a so-called PSD mass balance. This topic engenders much concern from manufacturers because the draft guidances for orally inhaled drug products include the recommendation as part of the product specification, the total mass of drug collected on all stages and accessories is recommended to be between 85 and 115% of label claim on a per [actuation/spray] basis.8,9 Taken in context with the entire recommendation, the FDA appears to be suggesting that PSD mass balance should be used as a determinant of the quality of the inhaler. Manufacturers have noted that both the acceptance criteria (85-115%) and the notion that mass balance be directly related to drug product quality are different from recommendations put forth by other standard setting bodies. For instance, the USP recommends that the total mass of drug collected in all of the components (material balance) divided by the total number of minimum recommended doses discharged is not less than 75% and not more than 125% of the average minimum recommended dose determined during testing for Uniformity of Dosage Units.18 Further, the USP notes that good analytical practice dictates that a complete mass-balance must be performed in order to confirm that all of the drug discharged from the inhaler was captured and measured in the induction portcascade impactor apparatus. This is not a test of the inhaler but serves to ensure that the test results are valid.18 It has also been recognized that PSD mass balance measurements, due to the complexity of the impactor and its use, may be subject to a great number of possible sources of error,33 and therefore failure of the PSD mass balance test may not be related to the integrity or quality of the inhaler. Thus, although there is little doubt of the importance of conducting PSD analyses during development to ascertain the respirable fraction of a given dose, there is much controversy regarding the utility of PSD mass balance measurements as an appropriate indication of the quality of the dose and therefore of the product. A consortium consisting of manufacturers of inhalation drug products, in collaboration with the Inhalation

Technology Focus Group of the AAPS,41 collected PSD mass balance data on products in development and on marketed products to investigate whether the FDA acceptance criteria was reasonable for inhalation products.42 From these data, the consortium concluded that orally inhaled drug products do not in general comply with the FDA mass balance requirement. The consortium further concluded that the mass balance requirement is not suitable as a drug product specification for quality but could be appropriate as a system suitability test. The report was submitted to FDA, and the issue was shortly thereafter taken on by the Product Quality Research Institute (PQRI).43 A PQRI working group consisting of experts from the FDA, academia, and industry was formed to investigate several key questions related to PSD mass balance for orally inhaled drug products (and also nasal sprays): (i) Does PSD mass balance, as a measure of the drug substance delivered per actuation, have a larger random uncertainty per determination than the dose content uniformity test?44 (ii) Does PSD mass balance deviate from the mean mass of drug substance delivered from the valve due to systematic uncertainties from multiple sources? (iii) Should mass balance acceptance criteria be based on data and method capability?34 Inherent in these questions is the larger question of whether mass balance is an appropriate test of product quality, and if not, what should the PSD mass balance measurement be used for in these types of products. A result of the working groups efforts is a recent publication describing good cascade impactor practices based on data describing all sources of PSD mass balance failures.33 In the paper, the working group suggested that PSD mass balance failures may not be linked to product quality and that a mass balance meeting acceptance criteria may only indicate that the given instrument collected the expected drug mass. Discussion within this working group on the utility of mass balance as an indicator of product quality is ongoing, with further conclusions to be published shortly. It is hoped that recommendations developed by this group will be used to provide guidelines for both pharmaceutical manufacturers and drug application reviewers. Control of Foreign Particles There is currently much interest from the FDA and manufacturers in developing regulatory guidance addressing foreign particles in orally inhaled drug products. The current FDA draft and final guidances for orally inhaled drug products, however, contain little information on this subject. Recently, industry conducted a survey of manufacturers to ascertain FDAs requests to companies regarding control of foreign particles in orally inhaled drug products.36 The results suggested that since the publication of the draft guidance regulatory expectations have evolved and continue to change. These changes seem a reasonable occurrence since regulation should evolve according to increasing and evolving scientific knowledge. However, the rationale behind some of FDAs expectations remains unclear. Curiously, it appears that one expectation from the agency for suspension MDIs involves control, enumeration, and identification of

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foreign particles greater than 10 m and greater than 25 m. As discussed earlier in this paper, it is unlikely that particles this large would enter the airways, depositing instead in the mouth or throat and entering the gastrointestinal (GI) tract. Industry has proposed that the safety issues associated with particles of this size should be assessed with respect to GI exposure and not lung exposure and that enumeration limits for particles in these sizes are best based on quality considerations for the product and therefore should be determined on a case-by-case basis.36 Additionally, discussion among industry and regulators is needed in understanding when in the pharmaceutical development process full characterization (e.g., determination of identity, shape, size, density) of foreign particles is best done. Because full characterization can be labor intensive and is often contracted out to specialized laboratories having the appropriate cleanroom facilities, manufacturers must consider control strategies that provide optimum efficiency as well as quality. Industry has suggested therefore that such characterization be performed early in the drug development process along with a rigorous understanding and development of control methods for all potential sources of foreign particles.36 FDAs expectations on this topic in published guidance are unclear, and further discussion among manufacturers and regulators is needed to clarify these expectations. Further information on the clinical relevance of foreign particles would also assist in development of scientifically sound guidance on control of foreign particles in inhalation dosage forms. The onus would appear to be on industry to obtain this information as it is difficult to ascertain clinical relevance without understanding the identity and nature of various foreign particles. Such information, however, is usually proprietary and difficult to publicize for encouraging broader discussion. It is hoped that science and experience-based discussions and investigations by industry, the FDA, and the scientific community will continue so that these questions may be addressed in the regulatory arena. Conclusion Particle science is of key importance in the development of orally inhaled drug products. Drug particle size and shape can influence the site of deposition into the lungs and therefore affect the quality, safety, and efficacy of the product. Examples of particle analysis for orally inhaled drug products include PSD analysis and control of foreign particles. The FDA has recommended that assessments of APSD mass balance and foreign particles be performed to determine product quality. Aspects of APSD mass balance are being discussed by industry, academic, and FDA scientists to develop scientifically sound guidance for orally inhaled drug products. Best practice approaches and investigations into the clinical relevance of inhaled OINDP foreign particles are being conducted by manufacturers. It is hoped that further discussions, as well as sharing of data and information, among manufacturers and regulators will result in scientifically sound regulatory guidance addressing PSD mass balance and approaches for control of foreign particles in OINDP.

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(32) For images and further descriptions of cascade impactors see http://www.copleyscientific.co.uk; http://www.thermo.com/com/cda/product/detail/1,1055,22485,00.html; http:// www.mspcorp.com/pharmaceutical.htm. (33) Christopher, D. et al. J. Aerosol Med. 2003, 16, pp 235247. (34) Work Plan: Establishment of the Appropriate Use of the Particle Size Distribution Mass Balance Determined by Cascade Impactor for Orally Inhaled and Nasal Drug Products; Product Quality Research Institute, Particle Size Distribution Mass Balance Working Group: Arlington, VA, 2002; http://www.pqri.org/minutes/pdfs/dptc/psdmbwg/ workplan02.pdf. (35) Christopher, D.; Pan, Z.; Lyapustina, S. Am. Pharm. Rev. 2004, 8, 68-72. (36) Blanchard, J. D.; Coleman, J.; DAbreu Hayling, C. Pharm. Res. 2004, 21, 2137-2147. (37) Oberdorster, G.; Ferin, J.; Lehnert, B. E. Environ. Health Perspect. 1994, 102, 173-179. (38) Brown, D. M.; Wilson, M. R.; MacNee, W.; Stone, V.; Donaldson, K. Toxicol. Appl. Pharmacol. 2001, 175, 191199. (39) Particulate Matter in Injections; general test chapter 788, USP 27-NF 22; United States Pharmacopeia: Rockville, MD, 2004.

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(40) Comments to Draft Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products, Chemistry, Manufacturing and Controls Documentation and Comments to Draft Guidance for Industry, Inhalation, Solution, Suspension and Spray, and Nasal Spray Drug Products, Chemistry, Manufacturing and Controls Documentation; International Pharmaceutical Aerosol Consortium on Regulation and Science: Washinton, D.C., 1999; http://www.ipacrs.com/topics.html. (41) American Association of Pharmaceutical Scientists. (42) Initial Assessment of the ITFG/IPAC Aerodynamic Particle Size Distribution Database by the CMC Specifications Technical Team of the ITFG/IPAC Collaboration; Inhalation Technology Focus Group of the American Association of Pharmaceutical Scientists/International Pharmaceutical Aerosol Consortium on Regulation and Science, 2000; http:// www.ipacrs.com/PDFs/Initial_Assess_of_Particle.PDF. (43) Product Quality Research Institute (PQRI), http:// www.pqri.org/. (44) The dose content uniformity test uses different techniques and methods and is developed specifically for capturing and measuring the amount of dose delivered per drug product actuation.

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