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The FDA has published draft guidance outlining its quality expectations for the development and manufacture of inhaled medicines.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.