International Pharmaceutical Aerosol Consortium Research Articles

Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS)

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.

Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Spray Pattern and Plume Geometry Testing and Methodology: An IPAC-RS Working Group Overview.

Plume characterization for orally inhaled and nasal drug products (OINDP) provides valuable information during OINDP development. Spray pattern and plume geometry techniques, methods, and technology have evolved over the past 20years since the publication of the original 1998 FDA MDI DPI draft guidance. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses the historical context and background to plume geometry and spray pattern characterization studies; provides an analysis of the current regulatory context; addresses results from its industry surveys on application and value of such testing; and presents case studies and best practices-seeking to provide insights to regulatory bodies and other stakeholders. Assessment and consideration of published studies and industry experience note the value of plume geometry and spray pattern in development, and that further data is needed regarding their use in assessing formulation characteristics. Continued dialogue between industry and regulatory bodies is needed to establish the optimum use of these techniques.

Reflections on Digital Health Tools for Respiratory Applications.

Background: In May 2019, the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) held a one-day workshop on digital health tools for respiratory therapies, with speakers representing views of patients, pharmaceutical and technology companies, physicians, and payors. Methods: Workshop presentations, audience discussions, and research of relevant literature form the basis of this article. Results: Conversations and publications to date illustrate the broad, and growing, interest in digital technologies, but also highlight a few gaps. The key messages are: (1) There are many great technologies, from simple to complex, but there is still an imperfect understanding of the problems that digital tools need to solve. The current approach often starts with a technology "solution" and then identifying the problems that it could address. This is a poor design practice: the offered technology may not represent the optimum solution to that problem; and that "problem" itself may not represent issues that patients or the health care system deem to be of high priority. (2) Respiratory medicine currently lacks widely accepted and easily measured biomarkers or hand-held diagnostic technologies that could be commercialized for complex/heterogeneous diseases such as asthma (unlike in other areas, e.g., diabetes). (3) There are no obvious solutions that integrate the perspectives of the many stakeholders-from patients to physicians to payors-to make the new field commercially viable, and the incentives of various parties in the health care system are misaligned. (4) A continued dialog, information sharing, mutual education, and collaborations are important in bringing the promise of digital respiratory medicine to fruition. Conclusions: Digital tools for diagnosis and management of respiratory conditions are an active area of research and development but long-term success in this field will depend on identifying real needs, and integrating the often-diverging interests of the various partners in each country's health care system.

Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs.

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.

European Regulatory Developments for Orally Inhaled and Nasal Drug Products.

Orally inhaled and nasal drug products (OINDP) are regulated in Europe via national (country) legislation and guidelines and/or legislation established in the European Union and resulting guidelines developed by the European Medicines Agency (EMA). Recent movement in EMA guidance and European Commission legislation implies potential significant changes in OINDP regulation. The UK exiting the European Union ("Brexit") has also raised a number of questions related to OINDP development and regulation in the region. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) European outreach working group provides and overview and analysis of the current state of European regulatory activity for OINDP (International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) 2018).

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.

Patient Focus and Regulatory Considerations for Inhalation Device Design: Report from the 2015 IPAC-RS/ISAM Workshop.

This article reports on discussions at the 2015 workshop cosponsored by the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) and the International Society for Aerosols in Medicine (ISAM), entitled "Regulatory and Patient Considerations for Inhalation Device Design, Development and Use." Key topics addressed at the workshop and presented here include patient-focused device design for orally inhaled products (OIPs), instructions for use (IFU), human factors, regulatory considerations in the United States and Europe, development of generic inhalers, quality-by-design, and change management of OIP devices. Workshop participants also identified several areas for further consideration and emphasized the need for increased focus on the patient to create therapeutic products (inclusive of device design, IFU, education, training) that support adherence with an individual patient's treatment regimen. Advances in patient-centric product development will require engagement and collaboration by industry, regulators, patients, physicians, and other stakeholders. The article includes summaries of presented talks as well as of panel and audience discussions.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Abstracts from The Aerosol Society Drug Delivery to the Lungs 25Edinburgh International Conference Centre Edinburgh, Scotland, UK December 10–12, 2014

Pharmacokinetic studies for proving bioequivalence of orally inhaled drug products-critical issues and concepts.

OPINION article Front. Pharmacol., 03 June 2015Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2015.00117

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference.

This article summarizes discussions at the March 2014 conference organized by the University of Florida (UF) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), entitled "Orlando Inhalation Conference: Approaches in International Regulation." The special focus of the conference was on global scientific and regulatory issues associated with the testing and demonstration of equivalence for the registration of orally inhaled drug products (OIDPs) in the United States, Europe, Brazil, China, and India. The scope included all types of OIDPs throughout their lifecycle, e.g., innovator/brand-name products, generics, modifications due to lifecycle management, device changes, etc. Details were presented for the U.S. "weight of evidence approach" for registration of generic products (which includes demonstration of in vitro and in vivo equivalence, as well as quantitative and qualitative sameness, and device similarity). The European "stepwise" approach was elucidated, and the thinking of regulatory agencies in the major emerging markets was clarified. The conference also highlighted a number of areas that would benefit from further research and discussion, especially around patient/device interface and human factor studies, statistical methods and criteria for demonstrating equivalence, the relative roles of in vivo and in vitro tests, and appropriate designs and metrics for in vivo studies of inhaled drugs.

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches.

This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications.

Quality Assurance Test of Delivered Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products–Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.

Foreign Particles Testing in Orally Inhaled and Nasal Drug Products

The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) presents this paper in order to contribute to public discussion regarding best approaches to foreign particles testing in orally inhaled and nasal drug products (OINDPs) and to help facilitate development of consensus views on this subject. We performed a comprehensive review of industry experience and best practices regarding foreign particles testing in OINDPs, reviewed current guidances and techniques, and considered health and safety perspectives. We also conducted and assessed results of an industry survey on U.S. Food and Drug Administration requirements for foreign particles testing. We provide here a result of our review and survey: a summary of industry best practices for testing and controlling foreign particles in OINDPs and proposals for developmental characterization and quality control strategies for foreign particles. We believe that clear consensus-based recommendations and standards for foreign particles testing and control in OINDPs are needed. The proposals contained in this paper could provide a starting point for developing such consensus recommendations and standards.

Modified two‐sided normal tolerance intervals for batch acceptance of dose uniformity

AbstractWe consider modified tolerance intervals for assessing content (dose) uniformity from one‐ and two‐stage designs. This work was motivated by a proposal from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC‐RS) to modify tolerance intervals to reduce their known conservatism away from the centre of the acceptance interval. IPAC‐RS's original proposal suffers from anti‐conservatism, but we find this is due to the choice of constants, not the form of the acceptance rule. We propose an alternative basis for choosing the constants in the acceptance rules and compare attained levels to those of other choices, including revised constants proposed by IPAC‐RS. These alternate choices of the constants lead to modified tolerance intervals that are either conservative at the sample sizes for which they were chosen or may have slight anti‐conservatism, within the limits of the simulations. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Chlorofluorocarbon to hydrofluoroalkane formulations: An industry perspective

The medications prescribed to treat asthma are provided in a range of delivery systems, designed to give patients a choice in how they take their inhaled medication. These include the mainstay of asthma therapy, the metered dose inhaler (MDI), and the breath-operated inhalers. One of the major challenges that all the leading companies in the respiratory area have faced in recent years is the environmental effects of chlorofluorocarbons. The pharmaceutical industry recognized the need to reformulate MDI products containing chlorofluorocarbons, and a number of companies began to develop alternatives in the late 1980s. To help facilitate this change in products, an industry consortium was formed (International Pharmaceutical Aerosol Consortium), and this has managed many of the overarching issues. After an extensive search was conducted, the most suitable alternatives were the hydrofluoroalkanes, which do not contain chlorine, are ozone friendly, and have lower global-warming potentials than the chlorofluorocarbons that they are replacing. To date it is estimated that the industry has invested over $1.0 billion ($US) on global research and development efforts. The first countries to launch the nonchlorofluorocarbon MDIs have been in Europe, and now salbutamol and 2 inhaled steroids are widely available across Europe in their nonchlorofluorocarbon form. Clinical testing has been extensive, and patient acceptance of the new products has proved to be high. Maintaining the smooth progress of the global transition is important, and continued dialogue between all key stakeholders should ensure success in this area. (J Allergy Clin Immunol 1999;104:S268-70.)

Metered Dose Inhaler Aerosol Deposition in a Model of the Human Respiratory System and a Comparison with Clinical Deposition Studies

Journal of Aerosol MedicineVol. 11, No. s1 International Society for Aerosols in Medicine Focus Symposium TOWARDS MEANINGFUL LABORATORY TESTS FOR EVALUATION OF PHARMACEUTICAL AEROSOLS Puerto Rico, January 29–31,1997Metered Dose Inhaler Aerosol Deposition in a Model of the Human Respiratory System and a Comparison with Clinical Deposition StudiesDAVID J. VELASQUEZ and BRIAN GABRI0DAVID J. VELASQUEZSearch for more papers by this author and BRIAN GABRI0Search for more papers by this authorPublished Online:25 Mar 2010https://doi.org/10.1089/jam.1998.11.Suppl_1.S-23AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byUse of Airway Replicas in Lung Delivery Applications Laleh Golshahi, Warren H. Finlay, and Herbert Wachtel30 March 2022 | Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 35, No. 2In vitro-in vivo correlations (IVIVCs) of deposition for drugs given by oral inhalationAdvanced Drug Delivery Reviews, Vol. 167Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs30 May 2019 | AAPS PharmSciTech, Vol. 20, No. 5Developing Ways to Evaluate in the Laboratory How Inhalation Devices Will Be Used by Patients and Care-Givers: The Need for Clinically Appropriate Testing4 June 2014 | AAPS PharmSciTech, Vol. 15, No. 5Improved laboratory test methods for orally inhaled productsTherapeutic Delivery, Vol. 4, No. 8Applying the AIM Concept in Support of Developing Improved In Vitro–In Vivo Relationships for OIPs25 February 2013Development of the Premature Infant Nose Throat-Model (PrINT-Model)—An Upper Airway Replica of a Premature Neonate for the Study of Aerosol DeliveryPediatric Research, Vol. 64, No. 2Studies of the Human Oropharyngeal Airspaces Using Magnetic Resonance Imaging. II. The Use of Three-Dimensional Gated MRI to Determine the Influence of Mouthpiece Diameter and Resistance of Inhalation Devices on the Oropharyngeal Airspace Geometry Susan E. Pritchard and Donald W. McRobbie11 January 2005 | Journal of Aerosol Medicine, Vol. 17, No. 4Entry Port Selection for Detecting Particle Size Differences in Metered Dose Inhaler Formulations Using Cascade Impaction2 February 2004 | Drug Development and Industrial Pharmacy, Vol. 30, No. 1Studies of the Human Oropharyngeal Airspaces using Magnetic Resonance Imaging. I. Validation of a Three-Dimensional MRI Method for Producing Ex Vivo Virtual and Physical Casts of the Oropharyngeal Airways During Inspiration Donald W. McRobbie, Susan Pritchard, and Rebecca A. Quest7 July 2004 | Journal of Aerosol Medicine, Vol. 16, No. 4The Sophia Anatomical Infant Nose-Throat (Saint) Model: A Valuable Tool to Study Aerosol Deposition in Infants Hettie M. Janssens, Johan C. de Jongste, Wytske J. Fokkens, Simon G.F. Robben, Kris Wouters, and Harm A.W.M. Tiddens7 July 2004 | Journal of Aerosol Medicine, Vol. 14, No. 4A new method to evaluate plume characteristics of hydrofluoroalkane and chlorofluorocarbon metered dose inhalersInternational Journal of Pharmaceutics, Vol. 186, No. 1Assessing lung deposition of inhaled medicationsRespiratory Medicine, Vol. 93, No. 2 Volume 11Issue s1Jun 1998 To cite this article:DAVID J. VELASQUEZ and BRIAN GABRI0.Metered Dose Inhaler Aerosol Deposition in a Model of the Human Respiratory System and a Comparison with Clinical Deposition Studies.Journal of Aerosol Medicine.Jun 1998.S-23-S-28.http://doi.org/10.1089/jam.1998.11.Suppl_1.S-23Published in Volume: 11 Issue s1: March 25, 2010PDF download

Introduction to the CFC Problem

ABSTRACT The history and progress of the Montreal Protocol negotiations and the formation, objectives and history of the Pharmaceutical Aerosol CFC Coalition (PACC) in the United States, and its European counterpart, the International Pharmaceutical Aerosol Consortium (IPAC) are discussed within the background of the essential medical use of CFCs in Metered Dose Inhalers.