Inhalation Product Research at FDA

Transcription

1 Inhalation Product Research at FDA Changning Guo Ph. D., Chemist Division of Pharmaceutical Analysis FDA/CDER/OPS/OTR 2016 GPhA CMC workshop, May 17, 2016 Disclaimer: This presentation reflects the views of the author and should not be construed to represent FDA s views or policies. 1

2 Office of Product Quality (OPQ) Office of Testing and Research (OTR) Division of Pharmaceutical Analysis (DPA) DPA Mission Statement Through biological, chemical, and/or physical assessments Provide a strong scientific and analytical base to support complex FDA investigations and enforcement actions. Provide leadership, and conduct and support programs, to ADVANCE and DISSEMINATE the application of new technologies and methods. 2

3 Recent Inhalation Research Projects Recent Finished Project: Abbreviated Impactor Measurement (AIM) Ongoing Projects: Bio-relevant Mouth-Throat Models Morphology Directed Raman Spectroscopy (MDRS) Polymorphic Transformation in Nasal Spray Suspension Products 3

4 Project I Evaluation of Abbreviated Impactor Measurement (AIM) Collaborate with OGD and OPQ/ONDP 4

5 Inhalation Testing Aerodynamic Particle Size Distribution (APSD) is the most relevant measure of the quality and effectiveness of inhalation products. Particle Size > 5 µm: Mouth and throat Particle Size between 1 and 5 µm: Lung Particle Size < 1 µm Inhale and exhale 5

6 Cascade Impaction The Gold standard for characterization of APSD. Extremely time/labor intensive, particularly when used for quality control and release of product. Andersen Cascade Impactor (ACI) Next Generation Pharmaceutical Impactor (NGI) 6

7 Problem Statement The pharmaceutical industry has proposed to FDA that methodology currently used to fully characterize orally inhaled drug products (OIDPs) during product development provides a level of detail that may not be necessary for routine quality control purposes. The current practice is highly resource and time intensive and, if this burden could be reduced on a per assay basis, additional assays could be conducted to better characterize a product batch. The proposal consists of suggested abbreviated instrumentation along with new metrics for the analysis of data generated from the proposed instrumentation. 7

8 Abbreviated Impactors Westch Fine Particle Dose Impactor (WFPD) Copley Fast Screening Impactor (FSI) 8

9 Reduced NGI (rngi) Rubber Stopper To Vacuum Pump Filter Placed on a mesh-screen Modified Cup 9

10 Research Findings The equivalency in Fine Particle Fraction (FPF) between the AIMs and full resolution impactors was observed for the MDI and DPI products tested in our study. It is advisable to evaluate the equivalency on a productby-product basis before implementing the simplified methodology for routine use in inhaler product characterization. Reference: Evaluation of an Abbreviated Impactor for Fine Particle Fraction (FPF) Determination of Metered Dose Inhalers (MDI). C. Guo, D. Ngo, S. Ahadi, W. H. Doub. AAPS PharmSciTech. (2013) Sep.14(3): Evaluation of Abbreviated Impactor Measurements (AIM) and Efficient Data Analysis (EDA) for Dry Powder Inhalers (DPIs) against the Full Resolution Next Generation Impactor (NGI). M. Mohan, S. Lee, C Guo, S. P. Peri, W. H. Doub. Manuscript in preparation. 10

11 Project II Evaluate Bio-relevant Mouth-Throat Models For Inhalation Drug Characterization Collaborate with OGD/ORS 11

12 Problem Statement For generic drug inhalers to be approved by FDA, bioequivalence (BE) with the innovator products must be demonstrated. Proof of BE is complex because the drugs used in these combination drug/device products are locally acting, and existing laboratory test methods fail to predict drug aerosol deposition in different airway regions. This study is designed to overcome this problem by developing and evaluating bio-relevant methods to characterize inhaled drug products using geometrically realistic mouth-throat (MT) models under realistic inhalation flow conditions. 12

13 USP Throat The United States Pharmacopeia induction port ( USP throat ) is used as a standard to connect the pharmaceutical inhaler device to a cascade impactor. The induction port is a 90-degree bend. 13

14 Bio-relevant throats Alberta Idealised Throat (AIT) Commercial product Realistic Mouth-Throat Model * Developed based on literature values and medical images Reference: 14

15 Flow rate Constant Flow (28.3 L/min, 60 L/min) Simulated breath pattern from clinical data Specific Aims Evaluate different types of MT models used in in vitro testing by comparing both the total delivered ex-throat and APSD of orally inhaled drug products. Evaluate the in vivo in vitro correlations for the tested MT models / flow conditions by comparing the experiment results with in vivo drug deposition has been reported in the clinical literature. 15

16 Project III Particle size characterization methods for active pharmaceutical ingredients (API) in suspension-based aqueous nasal spray products Collaborate with OGD/ORS/DTP 16

17 Background The rate and extent of drug availability to nasal sites of action, and to the systemic circulation are potentially influenced by drug substance particle size distribution (PSD). At present, there is a lack of established methods to characterize particle size of active pharmaceutical ingredients (API) in locally-acting suspension nasal spray products in which the API and one or more of the excipients are suspended in the formulation. 17

18 Emerging Technology for Particle Size Analysis of Nasal Spray Suspension Formulation ---Morphology Directed Raman Spectroscopy (MDRS) Malvern Morphology G3-ID Combines microscopic imaging and Raman spectroscopy in one integrated platform. Substance specific particle size determination (PSD) 18

19 Purpose Investigate suitability of MDRS method in determining PSD of APIs in currently marketed nasal suspension spray products. Specific Aim To develop and validate sample preparation and particle size characterization methods. Sample preparation method and optimum instrument set up will be validated for six commercially available aqueous nasal suspension spray products. 19

20 Project IV Development of Analytical Methods to Characterize Polymorphic Transformation and Particle Growth for Suspension based Nasal Spray Drug Products Collaborate with OPQ/OLDP 20

21 Background Polymorphic transformation and particle growth is a significant concern for nasal spray suspension products because it can have a negative impact on drug substance stability, drug product stability, and nasal spray performance. Particle size distribution / crystal growth and polymorphic form characterization in pharmaceutical suspension formulations have been a challenging topic for existing laboratory techniques. 21

22 Specific Aims Evaluate potential analytical methods in the literature that can best capture possible polymorphic transformation and particle growth in nasal spray drug products. Develop a 2 in 1 analytical method to identify drug substance polymorphic form and quantify amounts of each polymorphic form, and evaluate if particle size has increased in the nasal spray suspension products. Assess any transformation that may occur when challenging these formulations with low levels potential seeds to promote polymorphic form transformation. 22

23 Proposed Analytical Methods Morphology Directed Raman Spectroscopy (MDRS) XRPD Raman / IR DSC Proposed Test Conditions 5 weeks in-use condition --- controlled room temperature (25 C/60%RH) 3 months accelerated storage (40 C/75%RH). 4 weeks freeze-thaw temperature cycling (12-hour cycle between -20 C and 40 C) 23

24 Summary DPA is the primary laboratory in the Agency to provide inhalation research and testing support for all drug quality functions at CDER, including review, inspection, and research. Support the development of scientific standards and policies on the manufacturing and quality of inhalation drug products. Identify, evaluate, and develop technologies to assess the safety and efficacy of inhalation drug products. Address regulatory science needs in support of application review, facility evaluation, and surveillance and prepare for emerging science issues. Collaborate with external and internal stakeholders to advance internal knowledge, and develop novel technologies. 24

25 OTR/DPA facility at St. Louis, MO 25