The journey from early-phase clinical trials to successful commercial launch for an injectable drug product is complex and multifaceted.
When considering the delivery system, the choice between a traditional vial or prefilled syringe (PFS) and a modern autoinjector can significantly impact patient experience, adherence, and market competitiveness. Parallel development of both vials and prefilled syringes for autoinjector options, requires careful consideration to ensure regulatory compliance, patient safety, and commercial success. In this article, we explore the essential considerations for navigating the parallel development of a drug product in a vial, and a prefilled syringe for an autoinjector, together with the downstream final assembly and pack considerations from early-phase clinical trials to commercialization.
Pre-clinical and Early Phase Trials
Traditionally, intravenous administration of drug product using either a single or multi use vial would be the primary container of choice for biopharmaceutical companies for preclinical and early phase clinical trials. With the primary objectives being proof of concept, safety and tolerated dose, vials present a high degree of flexibility with respect to fill volume and applied dose, supporting the immediate need of speed through the clinic.
With a focus on patient-centricity and the increasing adoption of self-administration devices across various therapeutic areas for anaphylaxis, allergies, and lifestyle and chronic diseases such as psoriasis, diabetes, multiple sclerosis, and rheumatoid arthritis, biopharmaceutical companies are actively incorporating patient viable subcutaneous dosage forms such as prefilled syringes for autoinjector drug delivery technology into their product portfolios.
Recognizing the competitive advantage these devices offer in terms of differentiation, patient compliance and patient satisfaction, the autoinjector market is witnessing a surge in innovation. Biopharmaceutical companies are investing in research and development to not only enhance device features and compatibility with a diverse range of large and small molecule drug products, but they are also introducing and evaluating them as viable dosage forms earlier in clinical trials.
Balancing the Immediate with the Future: Parallel Development
Changing the method of administering a treatment during clinical trials, for instance, changing from intravenous (IV) to subcutaneous (SC) delivery, along with introducing a combination product, brings added complexity to both technical and clinical development plans. This necessitates additional clinical bridging studies, including assessments of bioavailability and safety, as well as technical comparability studies if adjustments are made to the concentration, pH, tonicity, or other critical quality attributes of the formulated drug product, adding time and additional costs to a development program. To address these challenges, biopharmaceutical companies are looking to parallel development strategies.
Parallel development in early phase clinical studies involves concurrent and coordinated advancement of both drug and container/device components from early stages through to commercialization. With the key objective of accelerating time to market, close collaboration between pharmaceutical development and injectable device packaging teams is essential to align goals and streamline processes.
Container Closure Studies
Parallel container studies are conducted during the development of drug products to compare the performance, stability, and compatibility of the product packaged in different container types. Evaluating multiple container closure system configurations early in the development lifecycle provides optimum flexibility and accelerates speed to market.
Specifically, when considering drug products packaged in vials versus prefilled syringes, parallel container studies aim to assess any differences in factors such as stability, container-material interactions, drug product integrity, and usability.
These studies involve packaging the same formulation of the drug product into both vials and prefilled syringes and subjecting them to a series of tests and evaluations. Below are some key aspects of parallel container studies for drug products in vials and prefilled syringes:
- Stability Testing: Both vials and prefilled syringes are subjected to stability testing under various storage conditions (e.g., temperature, humidity) to evaluate the degradation kinetics of the drug product. This helps determine whether there are any differences in stability between the two container types. Putting both vials and prefilled syringes down for stability during early phase trials provides access to almost 2+ years of stability data compared to beginning only with a vial format. So even if clinical trials are being conducted using a vial, stability data is being collected simultaneously on prefilled syringe presentations, buying time for later phase trials.
Similarly, autoinjector functional stability tests following ISO 11608-5 such as cap removal force, activation force, extended needle length, dose accuracy, injection time, lockout force can be conducted in parallel, saving valuable time should a decision be made in later phase trials to proceed with this method of drug delivery.
- Container-Drug Product Interaction Studies: These studies assess the compatibility of the drug product with the materials used in vials and prefilled syringes. They aim to identify any interactions between the drug product and the container that could affect product stability or efficacy safety. Photo-stability studies should also be initiated to evaluate drug product sensitivity to light.
The most critical aspect of primary packaging is for it to be as inert as possible so that it does not react with, add to, absorb, or allow external factors to change a drug product’s established safety, strength, quality, stability or purity characteristics. The material must be chemically stable, support the required concentration of the drug and not cause any extractables or leachables (E&L) issues, delaminate, or undergo other changes upon contact with the drug product.
- Container Closure Integrity Testing (CCIT): Container closure integrity is critical for maintaining the sterility and stability of the drug product. Both vials and prefilled syringes undergo testing to ensure that the closure system combination effectively prevents contamination and leakage. CCIT may be conducted in parallel with autoinjector functional stability testing.
- Usability and Human Factors Studies: Parallel studies may also include assessments of usability and patient preference between prefilled syringes and autoinjectors. Factors such as ease of handling, convenience, and patient comfort are evaluated to determine which container type may be preferred by end-users.
With patient-centric focus, interaction between users and the product as-received is paramount. Understanding how patients and healthcare professionals interact with the packaging, instructions for use (IFU), and the device itself is vital for optimizing usability, minimizing user errors, and enhancing overall safety, efficacy, and adherence to gain improved outcomes. (diagram two)
Conducting usability studies and incorporating human factors considerations early in the design process can help identify potential issues and inform design modifications. Human factors and usability engineering is an integral component of regulatory submissions and is essential for demonstrating the product’s usability and user comprehension.
- Regulatory Considerations: Parallel container studies are conducted in compliance with regulatory guidelines, which may vary depending on the geographic region. Regulatory authorities require comprehensive data demonstrating the comparability and suitability of both container types for the intended drug product.
Benefits of Parallel Development
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- Expedited timeline: Running drug and device development activities in parallel can significantly reduce the overall time to market by eliminating sequential processes and optimizing workflows.
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- Enhanced efficiency: Coordinated efforts and shared resources lead to improved efficiency in development activities, resulting in cost savings and faster decision-making. Streamlining processes and workflows leads to improved efficiency in resource utilization and decision-making.
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- Regulatory alignment: Aligning regulatory strategies for both drug and device elements early in the development process facilitates smoother regulatory approval and market entry.
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- Cost savings: Eliminating redundant activities and optimizing resource allocation can result in overall cost savings throughout the development lifecycle.
Parallel container studies provide valuable insights into the performance of drug products in vials and prefilled syringes, helping biopharmaceutical companies make informed decisions regarding primary packaging choices based on factors such as stability, compatibility, and patient preferences avoiding costly delays on the journey to commercialization.
Drug-Device Strategy
Data gathered and analyzed along the parallel container studies in early clinical trials eases the transition to prefilled syringes for later phase clinical trials. Typically at phase IIb clinical trials, biopharmaceutical companies seek to make decisions on the therapy’s drug-device strategy. Whether to continue with the prefilled syringe as-is, convert to a needle safety device, or insert into an autoinjector to provide ultimate flexibility for various health care professionals, patient populations, or reimbursement schemes.
Considering the Target Product Profile (TPP) / Quality Target Product Profile (QTPP), decisions can be made on whether there is a unique need for device innovation for specific patient populations or if traditional, readily available platforms would be suitable. Selecting established platforms that have received regulatory approval as part of a drug-device combination product previously, may be deemed lower risk for a new program (Table 1).
| Advantages | Disadvantages | |
| Established platform | • Lower upfront costs • Leverage of existing capital infrastructure • Smoother regulatory path • Robustness of device uses currently in the market |
• Limited product differentiation • Higher unit costs • Coemption of supply for popular devices |
| Proprietary platform | • Product differentiation – competitive advantage • Custom design for specific applications • Extend Intellectual Property (IP) life of the product • Lower unit costs when scale is achieved |
• Higher upfront costs, for example, design, IP, capital technology • Complex regulatory path |
Package Design for Manufacturability
To avoid unnecessary delays and additive costs, consultation between developers, clinical and commercial stakeholder groups is important throughout the parallel development lifecycle. Packaging design is a critical area of importance and so early consideration of manufacturability is encouraged. Considering package design earlier in the drug development process can lead to both cost and time efficiencies as the cost of mistakes can be considerable and delay product launch milestones. Ensuring that design and operational teams work together and by applying a design for manufacture philosophy, the teams will understand the impact of design on packaging operations earlier in the process, delivering a streamlined and longer-term efficient solution.
A common challenge often arises when a biopharmaceutical company has had their pack designed by a third-party design agency, which may fit the end-user specification and sponsor’s branding requirements, but then does not fit on existing packaging infrastructure when it comes to commercial manufacture. A designed pack that is not optimized for the packaging process equipment will result in unnecessary upfront capital costs, modifications to existing equipment and higher labour and commercialization costs, ultimately resulting in higher manufacturing costs and lowering commercial revenues.
Best Practices and Strategies
With many integral considerations when conducting parallel development of a novel drug product in vials and prefilled syringes for autoinjectors, there are several best practices to help ensure a smooth and efficient process, including:
• Early collaboration: Establishing cross-functional teams of all stakeholders involved in the development process, including formulation scientists, packaging engineers, regulatory experts, quality assurance professionals and patient focus groups. Fostering collaboration and communication from project initiation ensures alignment of goals, troubleshooting and efficient progress.
• Risk management: Proactively identifying and addressing potential risks, such as technical challenges or regulatory hurdles, helps mitigate delays and ensure project success.
• Iterative development: Embracing an iterative approach allows for continuous refinement and optimization based on feedback from user testing, regulatory feedback, and market insights.
• Regulatory compliance: Ensure compliance with regulatory requirements for both vials, prefilled syringes and autoinjectors in the target markets. This includes adherence to relevant guidelines for drug product packaging, device design, quality control, and documentation.
• Flexibility and Adaptability: Maintain flexibility and adaptability throughout the development process to accommodate any unforeseen challenges or changes in project requirements. Be prepared to adjust timelines, resources, and strategies as needed to optimize the parallel development of vials and prefilled syringes for autoinjectors.
Conclusion
Parallel development has emerged as a strategic approach to expedite the development process and bring innovative therapies in drug-devices such as autoinjectors to market faster. From early-phase clinical trials to successful commercial launch, considerations such as drug product device compatibility, manufacturability and packaging design must be carefully navigated. By addressing these considerations proactively and strategically, biopharmaceutical companies can streamline their clinical to commercial process and ultimately improve patient outcomes.
Authors:
Jeff Clement, Executive Director, Technical Sales – Development and Manufacturing
Bill Welch, Executive Director of Services, PCI Pharma Services
Accelerating Innovation: The Power of Parallel Development for an Autoinjector Launch with Jeff Clement, Executive Director, Technical Sales – Development and Manufacturing & Bill Welch, Executive Director of Services at PCI Pharma Services | As seen in OnDrug Delivery | May 2024.
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