Guest Column | May 29, 2024

EMA Updates Guidance On Inhalation And Nasal Product Quality

By Tim Sandle, Ph.D.

female doctor with nasal spray-GettyImages-1226391398

Inhalation and nasal medicinal products include pressurized metered-dose inhalers, dry powder inhalers, medicinal products for nebulization, non-pressurized metered-dose inhalers, nasal sprays, nasal powders, and nasal liquids. Both nasal spray and inhalation products usually include a delivery device, and the site of intended action of the active ingredient may be local or systemic.

These types of medicines are becoming more important given advantages they present over traditional dosage forms. Advantages include low first pass effect by hepatic metabolization, fast onset action, and high drug levels in brain tissue (via the nasal route) and lung (through oral inhalation).1

To help to further product quality and to protect patient safety, the European Medicines Agency (EMA) has issued a new draft guideline titled “Guideline on the pharmaceutical quality of inhalation and nasal medicinal products.”2 The draft addresses current thinking in relation to these types of pharmaceuticals. The draft seeks to replace the 2006 edition of the guidance3 as well as supplementary questions and answers posted on the EMA website.4 A companion document, “Guideline On The Requirements For Clinical Documentation for Orally Inhaled Products,” remains current.5

The issuing of the draft represents the second round of review; an earlier draft was issued for comment in 2017.6 Public consultation on the new draft guidance opened during April and it closes on Oct. 31, 2024.

Developments In Inhalation And Nasal Products

Since the EMA guidance was first issued, inhalation and nasal products have advanced considerably and the medicinal applications have increased in scope. Examples include nano-carrier-based nasal drug delivery systems designed for neurotherapeutic molecule delivery;7 nasal gels containing anticonvulsant medication for epilepsy treatment;8 and the electro-spraying of cisplatin into the lungs to treat bronchial carcinoma.9 In addition, there have been advances in inhaler technology to improve drug delivery.

Inhalation and nasal spray medicines require dedicated guidance documents from regulatory agencies partly because such products have more variable bioavailability than medicines delivered by other routes of administration. This arises because of variability in use, such as with the patient’s inspiratory flow pattern.

Areas Being Updated

The new draft contains several areas for proposed updates. These include dose proportionality, flow-rate dependency, stage grouping, and requirements on data for an inhalation spray and the spacer/holding chamber. In terms of product development, the draft explores the possibility of using new abbreviated methods to conduct intra- and inter-device variability for delivered dose uniformity.

Among the key sections are the following.

Active Substance

Inhalation and nasal products generally have active substances of synthetic or semi-synthetic origin. Important considerations are:

  • Particle size: For inhalation products containing an active substance that is not dissolved at any time during the finished product manufacture, storage, or use, the particle size of that active substance is a critical parameter.
    • Acceptable methods of particle size analysis include laser diffraction (based on scattered light signals detected by a photo-detector array).10 When the acceptance criteria are set, this should evaluate whether a consistent particle size distribution is present, expressed as the percentage of total particles in given size ranges.
    • The particle size ranges should relate to the acceptable performance of the medicine in vivo.
    • The assessment of particles should extend to any polymorphic forms of amorphous content that could affect the quality or performance of the active substance.
  • Drug activation: The micronization process to assure the required quality of the micronized active substance is critical and must be adequately described.
  • Microbiological quality must be controlled.


The guidance indicates that the full qualitative and quantitative composition of the medicine should include the detail of the excipients, such as the solvents and gases designed to provide physical and chemical stability and to deliver the dose efficiently. The quantities of both the active substance and excipient need to be expressed as concentrations per unit volume or weight, per container, and amount per actuation (the release of the active substance). Selecting the appropriate excipient can be challenging given the mechanical and chemical barriers that exit through the route of administration.11

Product Development

The section on pharmaceutical product development in the guidance has been updated to reflect quality by design options with the development studies. Such approaches require more than one batch and a sufficient number of replicates from each batch to be evaluated (assessment of both inter/intra batch variability). The guidance indicates that bracketing among different strengths or pack sizes can be used, provided this is adequately justified.

In terms of the tests to be conducted, the guidance lists a range of tests. Not all of these are required based on the product type, its intended use, and route of administration. There are four tests, however, that are required for all inhalation and nasal products. These are:

  1. Physical characterization: This requires an evaluation of those characteristics that could affect the homogeneity, reproducibility and performance of the product. This includes solubility, particle size, particle shape, density, rugosity, charge, polymorphic form and crystallinity.
  2. Minimum fill volume: This is based on the individual container’s minimum fill.
  3. Aerodynamic particle/droplet size distribution: This requirement is an assessment of each individual stage particle size distribution data in order to understand the variations in the delivered dose of the medicine. To develop a suitable critical quality attribute, both the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) must be calculated.
  4. Delivery device development: This requires an assessment of the device’s component materials and an understanding of the device manufacturing process, together with the mechanism of delivery in relation to the impact of the overall device upon the product performance characteristics. Of particular importance are the delivered dose and the fine particle dose.

Among the types of tests that apply to selected product types, the explanations for the requirements for leachable and extractable testing have been expanded. Particular care is required with regard to non-compendial plastic materials and rubber container closure components in the event that these react with the product (by “non-compendial,” I mean that such materials will not have a direct path for the validation approach).

Product Release

As with product development, the guidance lists a range of tests that might be required for product release, depending upon the type of product being manufactured. There are four test areas that apply to all types of inhalation and nasal products:

  1. Description: Product descriptions must include both the actuator and the dose counter.
  2. Assay: With release assays, there are different requirements for multidose medicinal products (assessing the amount of the active substance(s) per weight unit or per volume unit) and for single-dose medicinal products (assessing the active substance(s) as mass per dosage unit). In both cases, release assay limits of ±5% should apply.
  3. Fine particle dose: Fine particles are important with the product range since particles with a smaller aerodynamic diameter will reach the deeper lung regions. To assess these, the upper and lower limits on the results of pooled stages, corresponding to a particle size distribution of less than 5 μm, are assessed unless an alternative particle size is required.12
  4. Microbiological tests: The microbiological requirements, either overall bioburden, sterility, and/or screening for objectionable organisms, should be defined and assessed as per the product use and patient population. Microbiological considerations also will extend to the container-closure system.

Ongoing Assessment

The guidance contains sections on stability evaluation and for managing the product life cycle. Both of these sections have been extended. This includes managing any changes to the physicochemical state or thermodynamic activity of the active substance(s).

Exclusions To The Guidance

The draft guidance does not specifically cover areas of product quality that are detailed in ICH guidances, such as impurities, process validation, stability testing, and the setting of drug product specifications. The assessment of impurities is seemingly more developed within the U.S. FDA guidance, with clearer guidance for the laboratory evaluation. Neither does the guidance address testing aspects that are covered by European Pharmacopeia monographs, including priming studies and specific analytical testing procedures.


  1. Mehta PP, Fröhlich E, Khan R, Parihar A, Kumar CMS. Editorial: Advances in orally inhaled and nasal drug products (OINDPs). Front Pharmacol. 2023 Mar 31;14:1185609
  2. EMA. Guideline on the pharmaceutical quality of inhalation and nasal medicinal products, EMA/CHMP/20607/2024
  3. EMA. Guideline on pharmaceutical quality of inhalation and nasal products, EMEA/CHMP/QWP/49313/2005 Corr.
  4. EMA. Quality of medicines questions and answers: Part 2 Specific type of products at:
  5. EMA. Guideline On The Requirements For Clinical Documentation for Orally Inhaled Products, CPMP/EWP/4151/00 Rev. 1
  6. EMA Update on Quality Guidelines on Inhalation and Nasal Products, The Aerosol Society conference, 2017:
  7. Rajput A., Pingale P., Dhapte-Pawar V. (2022). Nasal delivery of neurotherapeutics via nanocarriers: Facets, aspects, and prospects. Front. Pharmacol. 13, 979682
  8. Dalvi A., Ravi P. R., Uppuluri C. T. (2022). Design and evaluation of rufinamide nanocrystals loaded thermoresponsive nasal in situ gelling system for improved drug distribution to brain. Front. Pharmacol. 13, 943772. 10.3389/fphar.2022.943772
  9. Ruzgys P., Böhringer S., Dokumaci A. S., Hari Y., Schürch C. M., Brühl F., et al. (2021). Electrospray mediated localized and targeted chemotherapy in a mouse model of lung cancer. Front. Pharmacol. 12, 643492
  10. Totoki S, Yamamoto G, Tsumoto K, Uchiyama S, Fukui K. Quantitative laser diffraction method for the assessment of protein subvisible particles. J Pharm Sci. 2015 104(2):618-26
  11. Yousry C, Goyal M, Gupta V. Excipients for Novel Inhaled Dosage Forms: An Overview. AAPS PharmSciTech. 2024 25(2):36. doi: 10.1208/s12249-024-02741-w
  12. Courrier H.M., Butz N., Vandamme T.F. Pulmonary Drug Delivery Systems: Recent Developments and Prospects. Crit. Rev. Ther. Drug Carr. Syst. 2002;19:64

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at