ISO 11608-1:2022 – Needle-based injection systems for medical use: a user’s perspective

In scope and out of scope

Before 2022, a prefilled syringe provided within an automated needle safety device may have been considered a combination product and therefore fall within scope of ISO 11608-1. This meant adding both complexity and the potential risk of failure for the exposed glass syringe when undergoing some of the required tests. ISO 11608-1:2022 now provides clarity that these product types fall under ISO 11040 only, notwithstanding consideration to ISO 23908 Sharps protection and ISO 11608-5 automated functions if the product dictates their inclusion in DV.

The ISO series map

A big and influential addition to ISO 11608-1 comes up front in the form of the ISO 11608 series road map. This takes the form of the flow chart (ISO 11608-1:2022 Figure 1) and captures the interaction between all the ISO 11608 parts (and additional associated ISOs), which are needed in the development and understanding of a needle injector system verification process. Notwithstanding these minimum requirements provided in the ISO, device manufacturers must also consider the application of design, manufacturing and user risk analysis to further populate pertinent, device-specific design requirements.

Design verification risk analysis

Throughout ISO 11608-1, risk assessment and analysis features more heavily compared to previous versions. Device manufacturers are now requested to provide the risk analysis and justification for decisions made during the planning and evaluation of DV. This includes the identification of primary functions, addition of requirements, specification setting, use of statistical confidence and sampling.

Risk assessment and justification is key to documenting the thought processes in many aspects of design, development and requirements. Of course, the inherent risk level accepted in a programme is highly dependent on the company or developer. A low-risk approach adds complexity, effort and time to a programme, but may lead to an easier route through approval and launch. Comparatively, a higher-risk approach can speed up development programmes, but may fall foul of design transfer to manufacturing, regulatory question, a higher number of complaints, recalls, product withdrawals, or, in the extreme, harm to users.

Method capability and validation

The inclusion of Sections 5.5 and 6.1 in ISO 11608-1 provides welcome guidance on the capability of the test methods and describes the validation approach and requirements, as well as an introduction to the uncertainty of measurement.

Test method validation for device tests can be difficult due to the nature of the equipment-device interactions and interfaces. From experience, it is the device construction, design and shape which impacts tests the most. Destructive tests can be particularly difficult to validate due to their inherent high variability and the absence of a repeatability element to the measurement.

Interestingly, the addition of a validation requirement for inspection or attribute tests in ISO 11608-1 provides a clear pathway for the validation of individuals performing these tests. In the case of visual inspection of defects, however, very careful consideration is still needed around how to generate and maintain an effective set of validation samples which represent “good” examples and ones incorporating various foreseeable visual defects of some form.

General design requirements

The general design requirements are the minimum backbone of a device developer’s design requirement document. In the 2022 version of ISO 11608-1, the added clarification of these requirements is a welcome addition.

When writing design requirements, it is important to be precise and unambiguous in the language used. Often, poorly written requirements can lead to misinterpretation and confusion in test method deliverables. When applying numerical specifications to requirements, it is important to consider the precision needed against the requirement. Highly precise DV requirements (which include the use of many significant figures), will have a profound impact on the requirements of the test method and the equipment used.

Not every requirement needs to be included as a test method. Considering how else a requirement can be verified may decrease the DV test burden and reliance. An example is how to capture the audible, visible and tactile feedback by the device during its use. Tactile and audible feedback is especially difficult as these can be overly subjective. Even if a measuring system could be developed for audible and tactile feedback, assigning and, moreover, justifying a numerical specification could be nearly impossible.

In these cases, it may be advantageous to look for alternative verification methods, such as verification by design intent. For example, this might involve a clear description of a design feature(s) and tolerance analysis demonstrating the physical intent to make a noise, or the description of use showing the device is in a specific (visual) and broadly different (tactile) configuration prior to and after injection.

The consequence of this is the need to skillfully word these requirements so that verification is possible by these methods. A requirement that states “the device will make a noise when setting a dose” may not be verifiable for the reasons given, even though the device should make that noise. Whereas, wording the requirement as “the design shall have features that provide indication by two means, visual and either tactile or audible, or both, during dose selection” can be verified and moreover truly links the requirement to the validation phase when the true user demographic is taken into account, capturing their “real life “experience of the design.

Definition of primary functions

ISO 11608-1 incorporates much more clarity on the definition and assessment of primary functions (including the differences between primary functions and essential performance requirements) from IEC 60601-1. It is expected that all characteristics, functions and operations need to be validated. To achieve an effective, well-considered DV protocol, it is important to consider how to assess a subset of these, selected as primary functions, during in use life, end of shelf life, after transportation simulation and at in-use conditions.

Functional stability

A new addition to the ISO discusses the requirements for function stability programmes is welcomed. The requirements needed to determine and qualify the shelf life of the drug regulatory guidance, such as The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Device functional stability and its implication on component, subassembly and device shelf life (component life post moulding), is however less established, until now. Annex D of ISO 11608-1 establishes the requirements of functional stability very well. There is still plenty of room to tailor the studies suggested in the ISO to the needs of the device and inclusive drug product.

One important point to consider in relation to this are the accelerated stability storage conditions for functional stability which are suggested, somewhat tortuously, in the ISO. ISO 11608-1 Annex D the ASTM F1980, which specifies an accelerated stability condition specific and justified for plastic components of 50°C, 55°c or 60°C (not more than 60°C) and a humidity of 45% to 55%. It also provides some explanation to justify these parameters, based on the properties of common thermoplastics, the usual material used in the bodies and mechanisms of needle based delivery devices apart from the glass primary drug container. These are non-ICH conditions and therefore are not extensively provided by stability storage contractors. It could therefore be challenging to find sufficient long term stability storage space. Adopting these accelerated conditions for device functional stability could make the regulatory stability study incorporating both the drug and device function stability programmes much more complex than is necessary.

The Arrhenius equation (the equation that shows the dependence of a chemical reaction on the absolute temperature and hence links acceleration to real-time stability conditions) does not include humidity as a parameter for accelerated stability assessment. It would, therefore, be hard to differentiate between the effects on plastic components stored at 50% RH against being stored at 60% RH and equivalent temperatures. For these reasons, it seems preferable to stick to accelerated conditions which are well established and justified, as in the ICH recommendations, when preparing a device functional stability protocol.

Summary

While there are many more changes in ISO 11608-1 that could be discussed, this blog has covered some of the key ones for device manufacturers to consider. Such a comprehensive update to this standard has been a welcome addition and addresses many areas of ambiguity or shortcomings in previous versions.

The updated standards provide a clear and comprehensive set of requirements for needle injection device verification within a risk-based management system and within a comprehensive roadmap of linked parts and associated standards.

ISO 11608-1:2022 is a great example of a thorough and detailed review and update of a key standard in the medical device world. By following it closely, the industry can continue to innovate in needle-based injection devices.