Chemical Particle Characterization in Respiratory Drug Products

Particle size plays a particularly significant role in inhalable drug production, due to particles from 2-15 µm settling in the alveolus. Therefore, regulatory agencies and manufacturers alike follow strict regulations regarding proper sizing and chemical specific detection of the useful active pharmaceutical ingredient (API) particles, as well as in the tight control of foreign particles in inhalable and nasal inhalable.

Particle size plays a particularly compelling role in inhalable spray drugs - OINDP.
Morphologically directed Raman spectroscopy is used to determine the chemically specific particle size distribution (CSPSD). This has an important impact on bioequivalence, and is consequently used for de-formulation studies of originator products.

Foreign Particulate Matter in Inhalables

Early studies on Dry Powder Inhalers (DPI) showed that more than 95% of all foreign particles are organic (plastic and fibers) by origin, and therefore cannot be attributed correctly to any substance found through SEM/EDS analysis.

Particle size and shape data directs the Raman spectroscopy, and delivers a chemical specific particle size distribution. rap.ID offers the world’s most efficient technical solutions to provide rapid and relevant information in regards of the API, or contamination particles from 2-10 µm.

  • Foreign particle status of formulations, agents and excipients; foreign particle load in administered doses
  • Method development and validation of foreign particle studies
  • Routine foreign particle monitoring and release testing of nasal spray suspensions
  • Testing for particulate matter release on capsules and inhaler parts
  • Quality assurance and foreign particle analytics in inhalable drugs
  • Cleanliness analyses for incoming inspection of inhaler component parts

rap.ID’s contract testing services provide API and FPM identification method development and validation, within an extremely short timeline. Contact us today to streamline your new drug application, ANDA and NDA regarding FPM assessment.

Dry Powder Inhaler Data

An overview of particle materials found during a 15 year investigation on Dry Powder Inhalers in 6 different products.

Foreign particle analysis Foreign Particles in Dry Powder Inhalers
foreign particulate Matter analysis dry powder Inhaler Data

Main Sources of Foreign Particulate Matter Recovered while Simulating Use for Three DPIs Foreign Particulate Matter

Particle Composition Source
Cellulose Assembly and transport of device components
Polymers Particles generated during of the device.
Carbon Manufacturing, assembly and transport of device components
Protein Manufacturing and assembly, associated with the lactose carrier.

1. During our studies no significant amount of FPM that might be considered dangerous (such as asbestos) was found.

2.  In some cases we concluded that the contamination profiles in a dry powder inhaler was strongly dependent on sampling point (dose number) in the file time of the device.

3. In one example, after the first couple of actuations, the particles chemical nature changed from larger cellulose particles and fragments to smaller polymer particles.

4. Polymer particles were typically found to originate from the device itself.

5. Regardless of the device life-stage, the most prevalent contaminants were cellulose, polymers, carbon and proteins.

6. Particles can be generated during device usage.

Publications

Krapf et al., (2017), Fast Approach for Chemically-Specific Particle Size Distribution of Active Pharmaceutical Ingredients in Nasal Spray Ranging from Submicron Particles to Agglomerates, RDD 2017

Valet, O., (2014), Common Foreign Particulate Matter from Dry Powder Inhalers: Chemical Composition of the Top Four Contaminations, RDD 2014

VALET, O., (2011), MDI Foreign Particulate Matter Raman Determination Method Validation According to ICH Parameters, RDD 2011, Vol 2, pp 419-424

VALET, O., et al., (2010),The Use of High Throughput Raman Microscopy for the Concurrent Size Determination and Chemical Characterization of Inhalation Particles, RDD 2010, Vol 3, pp 763-768

VALET, O., LANKERS, M., (2008), Automated Imaging Analysis coupled with Raman Identification of 0.5-5000 µm Particles – Particle Explorer, PSA 2008

Valet, O., Lankers, M., (2008), Measurement and Identification of Foreign Particles in a QbD Environment – Streamlining with Efficient Analytical Methods, RDD 2008, Vol 3, pp 723-726

VALET, O., LANKERS, M., (2008), Higher Yield and Quality through Particle Identification, Journal of the IEST, October 2008

CHAMARTHY, S., et al., (2007) Why Powders Don't Behave the Way We Want? Understanding How Surfaces of Pharmaceutical Powders Influence Functionality, RDD Europe 2007, Vol 1, pp 321-324

BLANCHARD, J., et al., (2007), Best Practices for Managing Quality and Safety of Foreign Particles in Orally Inhaled and Nasal Drug Products, and an Evaluation of Clinical Relevance, Pharmaceutical Research, Vol. 24, No. 3

VALET, O., HESS, U., (2007), Method for Foreign Particles Counting and Identification in a Cellulose Containing Suspension of a Nasal Spray Formulation, RDD Europe 2007, Vol 1, pp 325-328

Valet, O., Niemann, M., (2006), Qualification of the Particle Explorer System for Foreign Particles Counting and Identification in a Dry Powder Inhaler Product Based on IPAC-RS Recommendations, RDD 2006, Vol 3, pp 761-764

VALET, O., (2006), Automatische Partikelidentifikation - Aufklärung von Mikrometer Kontaminationen ab 500nm, rap.ID Particle Systems GmbH 

Niemann, M., Valet, O., (2005), Development of an Integrated Measurement System for Foreign Particles Testing in OINDP Based on IPAC-RS Recommendations, RDD Europe 2005, Vol 1, pp 181-184

RÖSCH, P., et. al., (2005) Chemotaxonomic Identification of Single Bacteria by Micro-Raman Spectroscopy: Application to Clean-Room-Relevant Biological Contaminations, Applied and Environmental Microbiology, March 2005

VALET, O., LANKERS, M., (2005) Automated Raman Spectroscopy of ambient Aerosols with Airborne Particle Explorer, AAAR 2005

KREHER, C., et al., (2004), Foreign Particle Characterization in Inhalation Drug Products: A Critical Comparison of Methods and Techniques, Respiratory Drug Delivery, IX p x-y

VALET, O., (2002), Made to Measure, Cleanroom Technology, Polygon Media

LANKERS, M., (2002), Determining particle composition: Consider the path to the source, Cleanrooms, PennWell

LEWANS, M., (2001), Fingerprinting particles "automatically” , CleanRooms Magazine, 9

VALET, O., (2001), Woher stammen Partikel, Reinraumtechnik, GIT-Verlag

VALET, O., (2001), Schnelle Materialbestimmung von Mikropartikeln, Laborzeitschrift, GIT-Verlag