Many new drugs require innovative devices such as autoinjectors for drug delivery. Medical device developer SHL Group discusses how to plan their development.
Looking at self-administration therapy trends, injectable drug delivery devices such as pen injectors, autoinjectors and needle-free injectors show significant growth potential. It is estimated that the market for pen systems and autoinjectors will reach US$870m (€654m) in 2013 and $1.07bn (€804m) in 2015.1 Industry analysts estimate that more than 30% of all new product submissions to the FDA are combination products.2 Among these, the autoinjector is one of the fastest emerging drug delivery solutions.
While the autoinjector is now considered commercially suitable for the delivery of therapeutic drugs, to develop such a device successfully requires detailed planning, combination product knowledge, regulatory awareness and close collaboration with a carefully chosen device manufacturer.
An autoinjector consists of a pre-filled syringe (PFS) or cartridge inside a device that applies enough force to inject fully the desired drug within the specified requirements. Both of these components are regulated and together define the autoinjector as a combination product.
The design of an autoinjector is affected by the primary packaging (PFS or cartridge) inside. The PFS has been widely used and biopharmaceutical companies are familiar with the associated concerns. However, integrating the PFS into an autoinjector brings new challenges that will involve education as well as a carefully chosen partnership.
With these interrelated variables, those who wish to venture into the autoinjector market will need to understand the core competencies that should be sought in a device partner, the overall development process and pitfalls that should be avoided as early as the planning stage. The extent of the joint effort between the biopharmaceutical and device companies determines the overall success of the project.
A biopharmaceutical company should initiate discussions both internally and with a potential device partner regarding possible final delivery platforms as early as Phase I of a drug’s clinical trials. Involving a device manufacturer early can help identify possible mechanical limitations and allow more time for customisations. At this point, items such as accessible internal resources and device partner key capabilities should be evaluated. A prepared team will be the first essential step towards the right direction.
The team assembled to lead an autoinjector project should first evaluate whether the following items are available internally:
Basic mechanical device knowledge: A biopharmaceutical company may have abundant experience working with therapeutic drugs and even introducing them into a PFS, but may have none in integrating them into an autoinjector. While finding a partner with the right expertise is crucial, obtaining basic mechanical device knowledge can help better prepare the team. Examples of the information that a standard specification may include are given in Table 1.
| Table 1: Examples of autoinjector device specifications | |
| Specification | Example |
| Delivered dose | 1.0mL |
| Viscosity range | 1-50cp depending on needle and injection time |
| Injection time | Over period span of seconds |
| Injector mechanism | Mechanical, electronic |
| Injection depth | Intramuscular, subcutaneous |
| Primary container | Prefilled syringe (PFS), standard or dual chamber cartridge |
| Activation method | Button activated, shield activated |
| Feedback mechanism | Audible, visual, tactile |
| Needle protection | Rigid/rubber needle shield, passive needle cover |
| Usage | Single dose, multiple dose |
| Dosage type | Fixed, variable |
| Needle attachment | Pre-attached, manually attached |
| Needle insertion/removal | Automatic, manual |
Regulatory experience: At least one member of the biopharmaceutical project team should be aware of all related regulations and establish a communication protocol with the device company early to ensure submissions do not delay timelines. Likewise, the device partner should have a team of regulatory experts and have experience of working with the FDA on combination product submissions as part of its core services.
With a prepared internal team now ready, the biopharmaceutical company can begin evaluating different device manufacturers as their potential secondary packaging partner. While many device companies have experience of working with autoinjector projects, only a few can provide the range of core competencies needed to successfully oversee the project from planning to launch.
The following list suggests attributes to look for when seeking a partner:
- An established track record and solid pipeline of autoinjector projects.
- A team of regulatory experts to support and co-ordinate regulatory aspects of the project.
- Knowledgeable project management teams to support and document all project phases.
- Strict and proven manufacturing quality control systems during all production stages.
- Strong in-house manufacturing capabilities and experienced operating personnel.
In-house manufacturing capabilities: these are vital when supporting design changes during scale-up or any other development stages. Some core capabilities to look for in a device partner include: tooling, moulding, assembly, automation, metrology and CNC machining.
Manufacturing an autoinjector requires complex processes and machinery. By having these capabilities available in-house, the device company will have full control of the development processes under one roof, ensuring quality and addressing design changes in a timely manner. Overall, a device company that can provide the above could have better insight of the development stages, product lifecycle and solid knowledge to better determine and manage project scopes.
Regulatory awareness: In addition to being familiar with regulations, the device partner’s regulatory team should have experience with similar projects and related submissions to provide insight and specialised considerations. Working with a partner that already has US FDA 510(k) clearance on device platforms can also significantly expedite the submission process.
Regulatory teams from both the device and biopharmaceutical companies will also need to communicate early and frequently
Regulatory teams from both the device and biopharmaceutical companies will also need to communicate early and frequently to define the intended use, indication for use, targeted markets and the corresponding regulatory pathway for final approval. Necessary documentation should also be available to meet the corresponding clinical trials and associated submission dates.
Systematic documentation: An autoinjector project can take on average 2-5 years to complete, so it becomes essential to establish a systematic documentation process internally beyond Document History File (DHF) regulations. This process should build towards a comprehensive knowledge bank, which can provide references for similar projects in the future. The implementation of such a system should be ready as early as the planning stages.
Post-market monitoring: The autoinjector is mainly distributed through hospitals and retail pharmacy portals. This adds a layer of complexity because, if not properly trained, the user can encounter difficulty due to incorrect usage. The product’s market performance can be directly affected if a thorough training and service programme is not in place. This programme should also include issue tracking processes along with report circulation to both parties for further review and troubleshooting.
Development: The unique administration requirements of every drug affect how the autoinjector device should be designed. As these requirements are translated into device specifications, the decision to customise an existing platform or to develop a new device needs to be made before the development stages. An ideal partner should be capable of providing assistance in assessing the route that best corresponds to the biopharmaceutical company’s business model.
Finding the balance between cost, time and the device design will be one of the major determining factors when finalising a suitable route. Choosing an existing platform allows further customisation and may cut time / cost associated with pre-study and prototype phases. A traditional development programme indicates a longer cycle but results in a brand new device that may better meet market demands.
Finding the balance between cost, time and the device design will be one of the major determining factors when finalising a suitable route
Regardless of the selected route, accurately defining design input requirements (DIRs) is vital to kick-start the development process. Finally, during the development phase, clear and constant communication is essential for a successful collaboration.
Design communication: The DIRs will serve as a communication tool to identify adjustments for the preliminary device prototype. It is a living document that will also be used to define critical process steps and testing parameters, ultimately affecting the set-up of the subsequent processes and key quality attributes.
At this stage, gaps between expectations and actual executions will emerge, making it imperative to hold regular meetings for solutions. Design control regulations will also need to be applied to define the design activities and changes and schedule formal design reviews.
Repeated adjustments during scale-up are expected and involve capabilities such as tooling and moulding, so it is vital to communicate new parameters accurately. To truly accomplish this requires housing core capabilities under one roof, as processes will be more streamlined.
Supporting adjustments with in-house capabilities: While some suppliers have in-house professionals for design, assembly and moulding, few have their own tooling and automation team to provide expert support on-site. With adjustments frequently required during development, owning these capabilities empowers the device company to address design changes quickly while ensuring quality.
Instead of executing each stage linearly, the availability of customised machines in-house allows for testing to take place once the corresponding designs and tooling are ready. Not only does this parallel process save significant time, it also eliminates additional risks and complexity associated with design and information transfers to outsourced vendors.
Figure 2: Planning checkpoints
Launch: While the biopharmaceutical company will be responsible for the commercial launch of the autoinjector, the partnership does not end here. Ideally, the launched autoinjector has already addressed most potential issues through a carefully designed and tested DIR, handling studies and quality control measures.
Nonetheless, user responses are unpredictable and concerns can still surface, especially with high volumes or when entering a new market segment. By the time the user receives the autoinjector, numerous variables aside from the mechanical design have been added that could have caused problems. Insufficient training or unclear instructions can also be a contributing factor.
Properly sorting and sharing reported issues can help the device manufacturer replicate scenarios and address potential causes. The final root causes are to be well documented in a knowledge inventory for both parties to refer to in the future.
In conclusion, when designing a combination product such as the autoinjector, insufficient planning and early conceptual design vulnerabilities can easily result in quality issues, prolonged project timeline and increased cost. It is imperative for the biopharmaceutical company not only to educate internal teams on the overall process flow early, but also to choose carefully a device manufacturing partner with an established track record, extensive regulatory experience and a wide range of in-house capabilities to support the ever-changing nature of the project.
Carefully analysing and trouble-shooting the device post-launch market responses and feedback is vital
During development, ensuring the design addresses critical quality attributes is key and can be achieved through close communication and vigilant DIR changes with the device partner. Understanding all associated regulations and timelines beforehand so that submissions do not become bottlenecks will also have an impact on time to market.
Finally, carefully analysing and trouble-shooting the device post-launch market responses and feedback is vital as user responses can reflect missing components in the original design requirement input and be considered as an additional parameter for second generation devices or similar projects in the future.
Mainstream use of the autoinjector will continue to grow as the demand for biologics and market competition increases. Under-standing the associated processes and challenges from planning to launch will be the first step towards project success.
references
1. Visiongain. (June, 2011). Pre-filled Syringes World Market Outlook 2011-2021. London, UK
2. Richter, S. (2011). Combination Products 2.0: Applying the New FDA Regulations. Agawam, Massachusetts: Microtest Laboratories.