Regulatory challenges of inhaler testing

The use of orally inhaled and nasal drug products to deliver both locally-acting and systemic therapies is on the increase; however, the regulatory requirements are challenging and in a constant state of evolution. Mark Copley discusses the methods used for DPI testing and the challenges presented by the current regulatory framework.

What is the regulatory approach for orally inhaled and nasal drug products (OINDPs)?
OINDPs are a class of products that includes dry powder (DPIs) and metered‑dose inhalers (MDIs), nebulizers and nasal sprays. Many of the tests suggested by the regulators for ensuring the safety, quality and efficacy of OINDPs are common to all pharmaceutical dosage forms. Tests for leachables, extractables and microbial contaminants, for example, are mandatory for all inhaled products. Of the tests that specifically relate to OINDPs, delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD) are universally accepted as being key parameters in assessing performance.

For MDIs and nasal sprays, these two parameters are often supplemented by tests to monitor the performance of the metering valve and actuator, such as spray pattern and plume geometry. This concurs with current regulatory thinking that the performance characteristics of OINDPs derive from the device and formulation in combination and underlines the need to test the product as a whole, rather than the individual components.

Consider, for example, DPIs: the design of the device dictates its unique flow resistance characteristics. For the vast majority of DPIs the motive force for drug delivery is provided solely by the patient and, therefore, the energy imparted depends on the strength and duration of the patient’s inspiration. If a patient were to use a device with a high resistance to air flow, the resulting flow rate through it would be much less than achieved by the same patient using a lower resistance device. Where delivery is successful, this air flow de-aggregates and disperses a dose of a pharmaceutical formulation into particles small enough for targeted deposition in the lung. However, whether or not a given flow rate achieves this goal depends on the properties of the powder formulation, in particular the strength of particle–particle interactions, and the delivery performance of the device. The combination of device and formulation is also relevant to the performance of liquid‑based systems such as MDIs and nasal sprays. In these cases, where the formulation may be held in a suspension or solution, properties such as viscosity and homogeneity tend to be important.

To confirm performance and manufacturing standards of OINDPs, the regulators recommend using in vitro test methods, which are designed to establish that the product consistently delivers the same quantity of API within a targeted aerodynamic particle size range. The first of these tests, DDU testing, collects and measures the total emitted dose of API under well-defined conditions. Measuring a specified number of shots at the beginning, middle and end of the life, for a multidose unit, determines consistency across the life span of the product. Assessing multiple devices from every batch produced provides prerelease quality control (QC).

APSD data can give a broad indication of the likely in vivo deposition behaviour of the drug, with a size of 5 μm or below being widely recognized as an approximate cut‑off diameter for penetration into the lung. Regulatory guidance recommends aerodynamic particle size measurement, using cascade impaction, for all OINDPs. Cascade impaction fractionates a sample on the basis of particle inertia, which is a function of aerodynamic particle size. Fractions are easily recovered from collection surfaces within the impactor for chemical analysis, allowing an APSD to be established, specific to the API.

It is important to understand, however, that a cascade impactor is not designed to simulate the lung; the deposition properties of which are extremely complex and difficult to replicate in vitro. The principal aim of cascade impaction is to obtain a relative measure of APSD for the emitted dose, rather than an absolute measure. Measurements ensure that the marketed product is similar to the product that was tested in clinic, for which regulatory approval was obtained.

Which bodies are responsible for developing and interpreting regulations?
The ultimate responsibility for the safety, quality and efficacy of medicines and medical devices lies with the various national regulatory bodies designated to safeguard public health.

In Europe and in the US, this function is performed by the EMEA and by the FDA, respectively. The principal guidelines relating to OINDPs are laid down by the EMEA^1,2 and the FDA^3–7. The regulatory authorities are supported in this role by:

• the Pharmacopoeia, whose job is to define the standards with which the drug formulation shall comply and the monographs by which compliance will be adjudged and
• in the case of OINDPs, by the International Standards Organization (ISO), whose function is to define the standards and methods relating to the medical device e.g., inhaler, nebuliser, etc. concerned. (see ISO27427:2009⁸ and ISO20072:2009⁹).

In 2002, the FDA launched a new initiative “Pharmaceutical cGMPs for the 21st Century” in which it proposed a new risk-based approach to pharmaceutical manufacturing. This initiative gave birth to Process Analytical Technology (PAT), a framework for understanding and improving the processes involved in pharmaceutical development, manufacturing and QC described in the FDA’s Guidance of September 2004.¹⁰. The goal of PAT is to ensure final product quality by understanding and controlling the processes involved in manufacture.

The Quality-by-Design (QbD) approach was agreed and recently adopted by the EMEA, the FDA and the Japanese Ministry of Health, Labour and Welfare (MHLW) in the form of the three quality related guidelines: ICH Q8, Q9 and Q10, published by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). These guidelines extend the PAT philosophy to all parts of the product cycle from product development, transfer through to manufacturing and finally the end product. ICH Q8 Pharmaceutical Development describes the suggested contents of a regulatory submission based on the QbD format. ICH Q9 details a systematic approach to quality risk management as applicable to the pharmaceutical industry. Finally, ICH Q10 describes a new quality management system for the pharmaceutical industry based on the complete product life cycle and referred to as the Pharmaceutical Quality System.

In addition to the above, mention should also be made of the contribution made by the following expert groups in establishing best practice and thinking on a range of subjects relating to OINDPs:

• European Pharmaceutical Aerosol Group (EPAG)
• International Pharmaceutical Consortium on Regulation and Science
• Product Quality Research Institute.

How is the regulatory framework changing?
Harmonization is an important trend as the ICH and the Global Harmonization Task Force, a body working specifically on medical device regulation, continue their activities. A potentially transformational change is the implementation of QbD, part of the risk‑based philosophy enshrined in ICH Q8, Q9 and Q10. QbD demands that quality is built in to a product from the outset, rather than tested for postmanufacture. It, therefore, challenges the industry to develop much greater understanding of both product and process, and requires relevant and effective manufacturing controls. QbD dovetails with the PAT initiative launched by the FDA¹⁰ to encourage the adoption of optimal process analytical techniques and instrumentation.

The evolving environment arising from the adoption of ICH Q8, Q9 and Q10 and the PAT initiative poses particular challenges for OINDP producers. However, the community is responding and one example of an important development is the introduction of the Abbreviated Impactor Measurement concept (AIM). While traditional multistage cascade impaction methods are highly valuable for the development and QC of OINDPs they are also time‑consuming, labour intensive and susceptible to analyst induced measurement variability. The AIM concept¹¹ addresses these issues, simplifying measurement by reducing the number of impaction stages, and hence size fractions collected, from the seven or eight normally associated with Next Generation (NGI) and Andersen Cascade Impactors (ACI). Suitable for QC and for rapid screening within the development environment, AIM in its simplest form splits the dose entering the impactor into simply a fine and a coarse particle fraction. The coarse particles are collected below the primary impaction stage and residual fines on a filter, similar to a multistage impactor. In the case of DPIs oversized particles and powder boluses are trapped in a preseparator before entering the impactor.

Splitting the dose into two fractions to give a fine and coarse particle mass (FPM, CPM) raises the issue of what to select as the cut-off diameter between the two. If, for example, the intention is to match guidance in the European Pharmacopoeia (Ph. Eur.) then the location of the boundary between the two fractions can be set at 5.0 μm. However, it is important to recognise that for product QC this value does not have to relate to clinical performance, in terms of likely deposition location. Recent research¹¹ has shown that the ratio of CPM to FPM is particularly sensitive to changes in APSD, especially as the cut-off diameter approaches the mass median aerodynamic diameter for the product of interest.

The AIM concept potentially provides a time-efficient, sensitive analytical solution for inhaler testing that complements multistage cascade impaction. Now it has been proven, commercial options for AIM are becoming available, although it should be noted that the concept still continues to evolve.¹¹ Regulatory approval for their use is expected to be on a formulation‑by‑formulation basis, relying on proven equivalence with established cascade impaction.

Elsewhere the regulators continue to refine and harmonize guidance in very specific areas: new advice relating to nebulizers is particularly noteworthy.

Guidance issued by the EMEA and Health Canada in 2006 has changed the regulatory approach for nebulizers in these countries, harmonizing it with the testing philosophy applied to other inhalation products. Historically, nebulizers were classified as medical devices and were used with a range of different drugs, as directed by the prescribing clinician. Consequently, they were tested as medical devices, in accordance with the European Committee for Standardisation Standard for Respiratory Therapy Equipment EN 13544-1. The new guidance recognizes that the safety and efficacy of a nebulized product depends on the drug/device combination and is supported by a new harmonized pharmacopoeial draft monograph published in Ph. Eur. Pharmeuropa,¹² and USP Pharmacopeial Forum.¹³ This defines a testing approach for DDU and APSD for the inhaled drug/device combination. The new standard ISO27427:2009,⁸ which supersedes EN13544-1, also includes this changed approach.

Unlike other types of inhaler, nebulizers operate continuously once loaded and the patient breathes normally to inhale the aerosolized product. Current test methods reflect this by recommending the use of a breathing simulator for DDU testing. Both ‘active substance delivery rate’ and ‘total active substance delivered’ are measured, usually under standardized flow conditions that reflect an adult breathing pattern.

The draft monograph and ISO standard also include a test method for ‘aerodynamic assessment of nebulized aerosols’, based on the NGI, which was calibrated for use at a flow rate of 15 L/min (typical of the mid-inhalation flow rate of a healthy adult) in an EPAG initiative in 2002. This extension to the original archival calibration^14,15 shows that the NGI meets nebulizer testing requirements, and provides guidance for use. The monograph addresses a number of issues associated with testing including, the possibility with some nebulizers/formulations that the thermal capacity of the impactor can cause evaporation of the droplets, leading to under-sizing, stage over-loading and re-entrainment.

What are the challenges posed by the changing regulatory approach?
While the adoption of new nebulizer guidance is straightforward, implementing QbD in the development and manufacture of OINDPs presents a unique challenge. QbD is significantly more complex for inhaled products than for other dosage forms because, for example:

• Product performance is a function of both device and formulation.
• A patient’s operating technique may influence the received dose.
• Product manufacture, and use, is influenced by environmental conditions.
• There is a lack of relevant real-time analytical tools.

These issues mean that the take-up of QbD for OINDPs may be relatively slow and may also depend on the development of new measurement techniques. One very pertinent issue within this debate is that clear in vitro–in vivo correlation is often absent, making it difficult to target clinical performance and/or demonstrate comparability or bioequivalence in a new or reformulated product. If, for example, a manufacturer chooses to switch to DPI delivery for an API, rather than reformulate a MDI (when a propellant is phased out, for instance), proving clinical equivalence is not straightforward. Conversely, starting development as if for a completely new product is very costly. Identifying new methods for demonstrating bioequivalence is, therefore, an important long-term goal for the inhalation product community.

Against this background it is fair to say that some companies remain unconvinced that the potential benefits of QbD, which include improved efficient, greater flexibility with regard to process changes and a lighter regulatory touch, outweigh the effort required to acquire the necessary knowledge for implementation. However, economic pressures on the industry are intense, and as the new approach becomes evident in submissions to the FDA it is possible that the regulatory response to those failing to change may harden.

References1. CPMP — Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (2006).
www.emea.europa.eu
2. CPMP — Points to consider on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP) (2004).
www.emea.europa.eu
3. FDA — Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products (1998).
www.fda.gov
4. FDA — Sterility Requirement for Aqueous-Based Drug Products for Oral Inhalation — Small Entity Compliance Guide (2001).
www.fda.gov
5. FDA — Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — Chemistry, Manufacturing, and Controls Documentation (2002).
www.fda.gov
6. FDA — Integration of Dose-Counting Mechanisms into MDI Drug Products (2003).
www.fda.gov
7. FDA — Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (1999).
www.fda.gov
8. ISO — ISO 27427:2009
www.iso.org
9. ISO — ISO 20072:2009
www.iso.org
10. FDA — PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (2004).
www.fda.gov
11. J.P. Mitchell, M.W. Nagel and M. Copley, Inhalation, 3(3), 26–30 (2009).
12. V. Marple et al., J. Aerosol Med., 16(3), 301–324 (2003).
13. V. Marple, et al., J. Aerosol Med.,17(4), 335–343 (2004).
14. Ph. Eur., Pharmeuropa, 18(2), 280–283 (April 2006).
15. USP Pharmacopeial Forum32(4) 1348–1352 (July–August 2006).