Key inhaler development regulatory guidelines for the generics market

06 Mar 2024 16min read

When developing a generic inhaler, it is essential for device developers to have a good understanding of the relevant regulatory requirements and international standards for bioequivalence, human factors usability and product quality. This understanding should ideally be established from the very beginning of the inhaler development project.

A note on generic inhalers

Inhalers allow delivery of medicine to the lung in the form of an aerosol of particles or droplets. The aerosol is generated either using stored energy (such as a pressurised gas) or by using patient inhalation airflow to disperse a powder dose. Either way, the patient inhalation airflow carries this medicinal aerosol into the lungs. These medicines typically treat respiratory diseases such as asthma and COPD, among others, or provide a route for systemic drug delivery via absorption into the bloodstream.

Generic products are sold as fully substitutable versions of existing reference products. Typically, the expiration of patents for any new medicines opens the door for generic versions to be marketed. Generic medicines have reduced development and clinical timescales compared to those of any new medicine, however there is a requirement to demonstrate the drug delivery device is also equivalent to the reference product in use and drug delivery.

What is bioequivalence and why is it important?

Achieving bioequivalence is the key challenge of developing any generic medicine. Bioequivalence means a demonstration that drug delivery, safety and efficacy of the generic product is demonstrably equivalent to that of the reference product.

For generic medicines to be accepted by regulators, they must closely match the reference product in both bioequivalence and usability. It is important to note that each regulator has slightly different definitions of what ‘equivalent’ means, which impacts the approach and data required.

In inhalation product development, small details in the device design can have a sizeable impact on product bioequivalence. Therefore, it is critical that device developers fully understand the key relevant regulatory guidelines and standards.


The challenges faced in demonstrating generic product bioequivalence

In the case of generic inhaler development, meeting the drug delivery bioequivalence targets can be very difficult indeed. The approval journey often has bumps in the road that are time-consuming and costly. To put this in perspective, one reference product, GSK’s Advair Diskus, was shown in a study to be inequivalent to itself across different batches. Generic pharmaceutical companies often face such variability in product manufacture and clinical trials, when trying to match their product to what could be a moving target.

For several legacy products, generic pharmaceutical companies seeking to copy the reference product have been asked by the regulators to gather additional data multiple times prior to gaining approval, resulting in a time-consuming and costly journey to market.

Why is use comparability important?

Demonstrating use comparability can pose similar difficulties. If there are differences in patient interactions with the generic compared to the reference device, then regulators may ask for user studies to demonstrate there are no negative impacts. While these challenges typically carry lower cost compared to a clinical study, they can contribute to project delays, particularly if device redesigns are required to mitigate arising usability issues.

Why is product quality important?

In addition to bioequivalence and use comparability, generic product developers must also meet the current regulatory requirements for ensuring product quality that apply to all inhaled medicines. Many of these requirements may not have been around at the time the reference product was developed, meaning even the reference product may not meet the latest requirements. Therefore, it is paramount that the development team has a good understanding of these regulatory requirements for bioequivalence, human factors usability comparability, and product quality.

ISO 20072:2013 provides some helpful inhaler-specific details for fulfilling product quality requirements, specifically around establishing and testing key features and functions through design verification. ISO 20072 differs from the regulatory documents and guidance in that it is more focused on mechanical functions required to enable drug delivery to the user, rather than drug delivery performance itself. These mechanical aspects are not as explicitly covered by the regulatory guidance documents, meaning device developers can use ISO 20072 to augment their programme of assessing the aerosol drug delivery performance and product usability.


Regulatory guidance for generic inhaler development

To provide a starting point for developing regulatory understanding, the FDA (USA Food and Drug Administration) and EMA (European Medicines Agency) offer several guidance documents for bioequivalence, human factors comparability and product quality. While the following sections do not provide an exhaustive list of all the relevant regulatory documents and standards it will be necessary to consult during medical device development, when used alongside ISO 20072 they provide a good starting point for developing a generic inhaler.

Bioequivalence regulatory guidelines

The EMA has a published guideline stating their requirements for demonstrating therapeutic equivalence (bioequivalence) between two inhalers for the treatment of asthma or COPD. Similarly, the FDA has published several drug product specific draft guidance documents setting out their expectations for demonstrating bioequivalence between two inhaled products. It should be noted that the FDA often takes several years to publish the final guidance documents but habitually publish draft guidance documents which are typically treated by regulators and industry as mandatory. Though these documents are primarily focused on pharmaceutical drug delivery outcomes, the device form and functions also play a critical role in meeting those pharmaceutical targets.

FDA standards for bioequivalence

The FDA sets high bioequivalence standards, requiring statistical equivalence to be demonstrated for in vitro benchtop product tests, clinical studies for both pharmacokinetic blood plasma drug levels (PK), and pharmacodynamic drug efficacy (PD). No safety PD data is required, apart from reporting of all adverse clinical events, since bioequivalence for PK is considered a sufficient demonstration that the generic product is as safe as the reference.

This ‘weight of evidence’ approach supports the FDA’s definition of bioequivalence, which requires data: “demonstrating an absence of a significant difference in the rate and extent to which the API [Active Pharmaceutical Ingredient] (or active moiety) in pharmaceutical equivalents becomes available at the site of action”. Since it is not possible to directly measure the dose within a patient’s lungs in a clinical study, these three datasets related to the lung dose are used together to minimise the risk of any differences in lung dose between the reference and generic products.

EMA standards for bioequivalence

The EMA, by contrast, sets out a stepwise approach with several alternative routes for demonstrating equivalence. Bioequivalence may be demonstrated solely through in vitro benchtop product tests, however, if the product does not achieve equivalence this way, then equivalence through clinical studies can be presented instead. In the first instance, this may be done through assessments of lung dose and distribution within the lung (e.g. radiographic imaging of appropriately labelled drug, or PK data). PD data on drug efficacy and safety is the final option if equivalence has not been demonstrated by these other routes. This approach supports the EMA’s definition of bioequivalence which is: “when two medicines release the same active ingredient into the body at the same rate and to the same extent under similar conditions.”

Impact of device design on in vitro bioequivalence

Device design is crucial for achieving a successful outcome demonstrating bioequivalent drug delivery to the reference product, with a potential impact on both in-vitro and clinical (PK and PD) measures. The suite of tests on which the device has most direct impact are the in vitro lab tests for Emitted Dose (ED) and Aerodynamic Particle Size Distribution (APSD) which have been demonstrated to have a relationship with the patient lung dose. Both the formulation and device contribute to these measures, therefore may impact in vitro bioequivalence outcomes.

For devices, factors such as the geometry of internal drug delivery pathways, surface roughness, electrostatic charge and seal to lab test equipment are all important considerations for ensuring equivalence. The EMA has defined equivalence limits and expect ED and the relevant APSD measures to be within ±15% of the reference product. It’s important to note that improvements in performance (which could for example include higher or lower ED) are not the aim here and would prevent the generic product from demonstrating bioequivalence with the reference. This would in turn necessitate additional clinical data and a different regulatory pathway.

Data demonstrating equivalence for device airflow resistance is required by both the EMA and FDA due to its effect on patient inspiratory flowrates while inhaling through the inhaler. Again, the EMA benchmark is for airflow resistance to be ±15% of the reference product, meaning the user experience of inhaling their medication should ‘feel’ the same as the reference product.

For pressurised metered dose inhalers and soft mist inhaler development, data is also required on the spray characteristics as well as the ability of users to reliably prepare the device for use. This is because the spray characteristics can impact the drug dose delivered to the lungs. For example, spray velocity and angle can determine the proportion of droplets which deposit in the mouth or throat or that pass through to the lung. Device internal geometry features, such as nozzle diameter, may have a large impact on achieving an optimal spray and effective drug delivery to the lungs.

Clinical measures, such as patient lung dose, PK and drug efficacy, depend on the measurable product performance indicators of ED, APSD and device airflow resistance. In addition, there may be harder to measure device impacts brought about by physiological and cognitive differences within a patient group. These might include how well a patient seals their lips against the mouthpiece, how engagement with the device mouthpiece impacts the patient’s mouth and throat geometry, and how the patient interprets the use instructions when inhaling through the device. It can also cover any handling and use errors which lead to unintended occlusion of air vents in the inhaler.

In the context of inhalation product development, the closer the generic device design matches the reference product, the better the chance of a successful clinical outcome. The FDA lists several device features that should be similar or comparable to the reference product, but these brief notes do not encompass everything that may impact clinical outcomes. Inhaler development teams will need to perform their own detailed risk analysis to achieve bioequivalence and ensure compliance.


Human factors use-comparability regulatory guidelines

The steps a patient must take to use their inhaler have a critical impact on drug delivery. The use sequence of a generic product must therefore also be shown to be comparable to the reference product. This is why the FDA has published draft guidance on how to assess and demonstrate use comparability between a reference and generic device.

In addition to the myriad impacts an inhaler device may have on clinical trial outcomes, it is necessary to consider the ability of patients to correctly take their dose each time without clinical supervision. For a generic device, steps to use a device must be comparable with that for the reference product.

The FDA guidance document states device developers should perform a threshold analysis to support this case. In this exercise, the use steps for the generic and reference devices are listed in full and any differences noted. If the differences are potentially impactful, it may be necessary to conduct user studies to determine if the generic product is substitutable with the reference product. It is important for healthcare professionals to have confidence when looking to switch a patient from the reference to the generic without any need for additional user training, which would therefore preclude its approval as a substitutable generic.

Quality engineering plays an important supportive role in meeting the human factors usability needs of patients. Data must be generated to ensure that user interfaces such as levers, covers and buttons (along with any associated operating forces, torques, or displacements) must perform reliably under a range of foreseeable use conditions. A device verification dataset such as this is essential to demonstrate that the generic device meets use-comparability requirements.

Product quality requirements

Beyond the imperative to demonstrate bioequivalence and use comparability for a generic medicine, it is also necessary to meet all the product quality requirements that apply to any inhaler seeking market approval. Many documents are associated with ensuring product quality, some of which are discussed below.

The FDA has published draft guidance outlining its quality expectations for the development and manufacture of inhaled medicines. While mainly focused on the pharmaceutical product, this includes a brief mention of requirements for devices. The EMA Medical Device Regulation (MDR) must be followed for all medical device developments, including those approved as part of a medicinal product. Annex I and II of the MDR helpfully itemise product technical performance and safety documentation and requirements.

The FDA and EMA both outline a risk-based approach to inhaler design, development and verification. These ensure that all risks are appropriately addressed, including a requirement that all manufacturing processes must be validated and be subject to ongoing process monitoring.

The EMA has also published a guideline on the quality documentation considerations for medicines that are delivered using a medical device. This contains the additional requirement that the rationale for device selection should be given, including its suitability for the medicine, the therapeutic indication and the relevant target patient population.

ISO standards also provide guidance on how to meet some of the regulatory requirements for product quality and risk management of inhalers. ISO 14971 outlines a risk management approach for medical devices and is formally recognised as harmonised by the EMA and FDA. ISO 20072 is not a harmonised standard but provides a very useful, detailed description of how to conduct design verification testing in inhaler development.

Key regulatory guidelines and standards such as these should be consulted early in inhalation product development, with a comprehensive list built as development activities scale-up, to ensure they are carefully followed and rationalised prior to attempting a submission.

ISO 20072 – device-specific considerations including design verification

The broad principles of ISO 20072 which describe requirements for the design, development, and verification testing of inhalers align well with those of the FDA and EMA, including confirming that a risk-based approach should be applied. The standard also provides inhaler-specific details that are missing from the broader regulatory guideline documents.

It should be noted that there are differences in the details between ISO 20072 and the FDA and EMA product quality requirements, for example in the environmental challenge conditions. Device developers will need to justify their decisions about how to navigate areas of ambiguity or conflicting requirements. It is important to note that ISO 20072 is focused on inhaler design verification and is agnostic to whether it is a novel design or generic. So does not give any details on the bioequivalence and human factors requirements that should be central to any generic medicine development.

ISO 20072 states that those device features critical to the safety and efficacy of the medicine should be identified based on the outcomes of a product risk assessment conducted following ISO 14971. It lists suggestions for key features and functions that the device must embody, with the expectation that testing and analysis is required to demonstrate the inhaler reliably meets requirements such as airflow resistance, controlled forces to operate, repeatable dose delivery, or accurate dose indication feedback.

The standard describes several environmental challenge conditions, covering scenarios which could represent ‘in use’ and ‘extreme use’ cases. The expectation is that devices are exposed to the conditions which are relevant to its embodiment, while demonstrating robustness and reliability in key mechanical functions.

In addition to device function, following successful completion of an inhaler design verification programme as described above, ISO 20072 requires that ED and, where applicable, APSD testing, be completed through a programme of ‘system verification’, with the scope determined by the device’s risk assessment and instructions for use.


Achieving regulatory compliance in generic inhaler development

With a good understanding of FDA and EMA expectations for demonstrating bioequivalence, human factors comparability and product quality, a clear roadmap can be drawn to guide the development of a generic inhaler and ensure the regulatory expectations are always considered. This does not guarantee success, since an aerosol drug delivery product development programme inevitably brings many challenges. However, having a clear view of the latest relevant regulatory guidelines and standards is still invaluable in helping device developers achieve a successful product launch.

Notes on regulatory documents and standards


  • FDA – Product-Specific Guidances for Generic Drug Development
  • EMA – Guideline on Bioequivalence for Orally Inhaled Products for Asthma & COPD

Human factors

  • FDA – Draft Guidance on Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA: Draft Guidance for Industry, 2017

Product quality

  • FDA – Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations Guidance for Industry (2018)
  • EMA – Guideline on quality documentation for medicinal products when used with a medical device.
  • EMA – Regulation (EU) 2017/745 of the European Parliament and of the Council on Medical Devices
  • ISO 20072 – Aerosol drug delivery device design verification. Requirements and test methods (2013)
  • ISO 14971 – Medical devices. Application of risk management to medical devices (20210


This article was taken from Team Consulting’s Insight magazine. Sign up for your own copy here.

Join the conversation

Looking for industry insights? Click below to get our opinions and thoughts into the world of
medical devices and healthcare.