Paul Barr, Chemistry Consultant at Broughton, outlines the key aspects of stability studies and explains why outsourcing is a compelling option for pharmaceutical manufacturers.
According to NHS figures, more than 12 million people in the UK — approximately one in five of the population — are currently affected by lung disease and, every year, more than 60 million inhalers are prescribed as a key form of treatment.1
Using inhalation as a drug delivery method can be traced back to 1929 when epinephrine was used to treat asthma.2 Since then, inhaled drug delivery has become widespread as a way to deliver medicines for lung disease and some systemic conditions.
This is because of its advantages, including the ability to directly target the lungs and the fact that inhaled medicines are rapidly absorbed into oxygenated blood; this enables the use of lower doses and can result in fewer side-effects.
Globally, more than half a billion people suffer from respiratory diseases, with 328 million people suffering from chronic obstructive pulmonary disease (COPD) and a further 262 million people affected by asthma — meaning the potential market for inhalation therapy is vast.3
Types of device
Inhalation therapy is traditionally performed by four types of devices: pressurised metered dose inhalers (pMDIs), soft mist inhalers (SMIs), dry powder inhalers (DPIs) and nebulisers.
Since their introduction in 1956, the pMDI has been the dominant method of treating respiratory diseases such as asthma and COPD. A search of the IQVIA database shows that, in the 12 months prior to June 2019, more than 480 million were prescribed.4
The prevalence of pMDIs is related to their economics; they are, for example, cheaper to produce than DPIs. Some studies also show that they may result in better outcomes, depending on the condition being treated.
A 2019 study found that switching from DPIs to pMDIs was associated with decreased asthma exacerbations and improved control.5
Safe, stable pMDIs
Stability studies are used to determine the shelf-life of a pMDI as well as establish its active ingredient efficacy and long-term safety. These studies provide essential evidence for regulators and the data obtained will be included in the clinical trial dossier.
Stability studies involve placing pMDI samples (within their container closure system and any other packaging) in various orientations into environmentally controlled chambers to determine how the drug product will change with time.
During the study, samples will be periodically assessed for changes in physical, chemical, biological or microbial composition, according to the study protocol.
Key areas
pMDI-specific parameters that are covered by stability studies include delivered dose uniformity (DDU); this is a measure that ensures that the patient consistently receives the correct dose throughout the inhaler’s lifecycle and between different inhalers.
DDU directly impacts the drug's efficacy and, consequently, will affect the therapeutic effect for the patient. It must therefore comply with strict pharmacopeial limits.
Another key metric for pMDI safety is its aerodynamic particle size distribution (APSD). A test is done to measure the particle size of the drug product while entrained in an air flow. This helps to determine which area of the lung the drug is delivered to.
Lung deposition affects bioavailability, which in turn impacts the drug’s therapeutic effect; so, ensuring that the aerodynamic particle size is within specification during product’s entire shelf--life is an important factor.
Another crucial aspect for pMDI safety is addressing the potential for moisture ingress during the device’s shelf-life.
For solution-based pMDIs, for example, wherein the drug is dissolved in an organic component such as ethanol, moisture ingress may affect the solubility of the drug in the solvent and cause partitioning and precipitation of the API; this may result in a drop in concentration and, subsequently, a reduced dose.
Another concern with moisture uptake is that it can increase the risk of microbial growth. This is a serious consideration for stability studies of all forms of drug delivery.
Owing to the route of delivery, however, microbial growth is a considerable risk and is tightly controlled via pharmacopeial limits for inhalation products.
For liquid formulations such as pMDIs, water ingress will also impact the leachables profile. Leachables may be compounds of toxicological concern or they may cause reactions within the drug formulation, potentially creating new chemical entities that may be of toxicological concern or adversely react with the API.
Naturally, oxygen will also be present when moisture ingress occurs in inhaled medicine products. The combination of higher humidity and oxygen can promote degradation of the product formulation.
Any deterioration of the API may result in decreased efficacy of the product as the label claim and DDU will change. Also, degradation can cause increased levels of breakdown products, which may be a toxicological concern.
Manufacturers will also have to consider storage positioning as part of their stability studies. pMDIs, for example, may be influenced directly by their orientation during their shelf-life because of their mode of operation.
Long-term stability of the actuator device is another important consideration as the device may not generate the correct dose and aerosol properties if it is not functioning correctly.
This could be because of degradation or changes to the device’s material or quality. Quality can be built into these products with the right type of packaging and container closure system and consistently evaluated with robustly designed stability studies to assess the critical quality parameters of the products.
Outsourcing stability studies
Stability testing is a specialist field; if a company does not have in-house experts for method development and validation, outsourcing may be a good solution. Selecting the right partner for stability studies is key, as some have broader expertise than others.
Outsourcing stability studies can give manufacturers access to subject matter experts, such as analytical chemists and toxicologists, who can help to complete test data analysis, understand deviations and troubleshoot problems.
If your testing partner is also an expert in extractables and leachables (E&L), studies can be run in parallel, thereby streamlining the route-to-market.
References
- www.england.nhs.uk/blog/delivering-high-quality-low-carbon-respiratory-care/.
- J.L. Rau, “The Inhalation of Drugs: Advantages and Problems,” Respir. Care 50(3), 367–382 (2005).
- M.V. Puci, et al., “Asthma, COPD, Respiratory and Allergic Health Effects in an Adult Population Living near an Italian Refinery: A Cross-Sectional Study,” Healthcare (Basel) 11(7), 1037 (2023).
- J. Pritchard, “The Climate is Changing for Metered-Dose Inhalers and Action is Needed,” Drug Design, Development and Therapy 14, 3043–3055 (2020).
- H.S. Park, et al., “Real-Life Effectiveness of Inhaler Device Switch from Dry Powder Inhalers to Pressurized Metred-Dose Inhalers in Patients with Asthma Treated with ICS/LABA,” Respirology 24(10), 972–979 (2019).