WHAT ANALYTICAL TESTING IS APPROPRIATE?
Bringing any type of OIP to the market requires progressing through several stages of development from initial concept to post market surveillance. Laboratory-based (in vitro) performance testing has an important role to play in this process, in early development of the concept including screening of candidate drug entities as part of formulation development, through the phases associated with product registration with the regulatory agency to ongoing batch release testing (1). Broadly speaking, though, there are two distinct streams related to the primary purpose for testing (2); (a) methods appropriate for assessing product quality, and (b) procedures providing data to support the clinical program (Figure 2).
WHAT TEST PROCEDURES IN THE US PHARMACOPEIA (USP) ARE PERTINENT?
There are several procedures for determining the several product general quality attributes covered in USP mandatory chapter <5> ((3) Table 1). However, these test methods are focused on defining the specific dosage form, and except for spray pattern (geometry) for some inhaler formats (i.e; pMDIs (termed inhalation aerosols)), do not require the aerosol to be generated. Methods covering the characterization of performance quality attributes of the medication-containing aerosol, that is the focus of this overview, can be found in mandatory USP chapter <601> (Table 1). These procedures are undertaken to quantify two critical quality attributes, delivered dose uniformity (DDU) and emitted aerosol aerodynamic particle size distribution (APSD). In addition, informative chapters <1601> and <1602> provide slightly more elaborate methods that include breath simulation for characterizing equivalent aerosol metrics for products for nebulization and S/VHCs respectively (Table 2). Additional support pertinent to all the methods for product performance quality is provided in chapters <1603>: Good Cascade Impactor Practices, and <1604>: Interpretation of cascade impactor derived APSD data.
The main purpose of the procedures related to product quality is to achieve simplicity in execution consistent with optimal precision, accuracy, and robustness. Fundamentally, they are designed to avoid out-of-specification occurrences and associated follow-up investigations for cause. Ideally, in batch release testing, substandard product (Type-1 error) that could affect patient efficacy/safety should always be detected, whilst there should be no false positive events (Type-2 error) resulting in product waste. Furthermore, although they should be indicative of clinical performance, the need is paramount for the sponsor to quantify the stringent quality control measures based on the product specification agreed with the appropriate regulatory agency/ies.
WHAT ARE LIMITATIONS OF TESTING FOR PRODUCT QUALITY CONTROL?
The limitations with the pharmacopeial performance quality aerosol characterization methods are as follows:
1. Use of a highly standardized right-angle bend as entry (induction port) to the aerosol sampling arrangement (dose uniformity sampling apparatus for DDU, multistage cascade impactor with/without preseparator for APSD),
2. Fixed flow rate sampling of the aerosol for all formats except DPIs, to enable the cascade impactor to operate with fixed stage particle size fractionation cut-point sizes.
3. Highly standardized procedure for DPI testing involving a rapid ramp up from zero to the final stable flow rate based on inhaler flow resistance for aerosol generation and dispersion as would occur by patient inhalation,
4. Lack of a patient interface for products with a facemask rather than a mouthpiece.
WHAT CHANGES DO MORE CLINICALLY APPROPRIATE METHODS INVOLVE?
The arrival of more generic orally inhaled products and the need to demonstrate in vitro equivalence to an innovator product is a driver for more clinically realistic methods (1, 4), as is increased awareness of the advantages where laboratory-generated data can be made more supportive of the clinical program (3). Each of the limitations of the quality control measurement methods outlined above have therefore been addressed as follows:
1. Replacement of the induction port with an age-appropriate anatomically accurate or idealized realizations of the oropharyngeal region. The induction port acts as a largely impaction-based filter retaining coarser particles, and allowing the bulk of the finer aerosol containing particles smaller than about 5 μm aerodynamic diameter to reach the target region of the airways of the lungs,
2. Use of age-appropriate breath simulation, involving slow inhalation followed by a breath-hold for pMDI and SMI products, a forced inhalation for DPIs or tidal breathing for nebulizers,
3. Insertion of a mixing inlet between the model oropharynx and the entry to the preseparator (if present) and/or cascade impactor. A mixing inlet allows for an external variable flow of air that can be generated by a breathing simulator to be combined with the aerosol flow exiting the inlet without affecting particle transport to the impactor. The impactor operates at a fixed flow rate, as designed, throughout the measurement period, regardless of the inhaler class being evaluated (Figure 3),
4. Incorporation of an age-appropriate face model with realistic skin and underlying tissue rendering. Such a model incorporates an anatomic or idealized ororpharynx (nasopharynx for obligate infant nasal breathing patients) as a further refinement that adds realism by being able to simulate potential pathways for ambient air ingress via often small leakage pathways during inhalation that can have a significant impact on aerosol transport past the facemask (5).
REALIZING THE TWO COMPLEMENTARY APPROACHES FOR OIP TESTING
From the foregoing, it should be evident that the two approaches for OIP performance testing can continue to exist side-by-side. In this context, for several years, the FDA has been supporting several research programs associated with the clinically appropriate stream through funding earmarked from the Generic Drug User Fee Amendments (GDUFA) program (6) whilst continuing to issue guidance to industry for several OIP forms that refers to the mandatory chapters in the USP (7). Likewise, in Europe, there is encouraging support for such methods from the European Medicines Agency (EMA) (8). Finally, there are precedents already in the USP (3) for some of the measures outlined above when evaluating products for nebulization (USP <1601>) or spacers and valved holding chambers for use with pMDIs (USP <1602).
REFERENCES
- Forbes B, Bäckman P, Christopher D, Dolovich M, Li BV, Morgan B. In vitro testing for orally inhaled products: Developments in science-based regulatory approaches. AAPS J, 2015; 17(4): 837-852.
- Mitchell JP, Suggett JA. Developing ways to evaluate in the laboratory How inhalation devices will be used by patients and care-givers: The need for clinically appropriate testing. AAPS PharmSciTech. 2014; 15(5): 1275-1291.
- United States Pharmacopeial Convention. United States Pharmacopeia (USP). Rockville, MD, USA. Visited October 18, 2023.
- Lee SL, Saluja B, Garcia-Arieta A, Santos GML, Li Y, Lu S, et al. Regulatory considerations for approval of generic inhalation drug products in the US, EU, Brazil, China, and India. AAPS J. 2015: 17(5): 1285-1304.
- Esposito-Festen JE, Ates B, Van Vliet FLM, Verbraak AFM, de Jongste JC, Tiddens HAWM. Effect of a facemask leak on aerosol delivery from a pMDI-spacer system. J Aerosol Med. 2004; 17(1): 1–6.
- US Food and Drug Administration (FDA). FY 2022 Science and research report. Silver Spring, MD, USA. Visited October 18 2023.
- US Food and Drug Administration (FDA). Metered dose inhaler (MDI) and dry powder inhaler (DPI) products: Quality considerations Draft guidance for industry. April 2018. Silver Spring, MD, USA. Visited October 18 2023.
- European Medicines Agency (EMA): Requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. London, UK. CPMP/EWP/4151/00 Rev. 1, 2009. Visited October 18 2023.