From Vial To Prefilled Syringe: Mastering The Development Transition

By Fran DeGrazio, Senior Industry & Technical Advisor, Drug Delivery Leader

A major trend in the injectable biopharmaceutical industry is the shift toward launching new drugs in prefilled syringe (PFS) formats. This approach is also increasingly used during lifecycle management for products that are already approved, offering a way to modernize delivery while building on an established therapeutic foundation.

Historically, new products were commercialized in vials. This was the easiest and most straightforward way of getting a drug or biopharmaceutical approved from a regulatory standpoint. However, this approach is not the best way to minimize preventable use errors that could lead to patient injuries.

An additional key driver of this shift from vial to PFS is the potential to improve patient satisfaction and quality of life. Prefilled syringes support self-administration, but the broader enabler of that is the transition from intravenous (IV) delivery, typically performed in a hospital or clinic, to subcutaneous (sub-Q) administration that patients can manage at home.

So, the incentives to move from vial-based to PFS-based product development are there. The question is how to align operations around this transition. In recent experience, I have seen a lack of understanding, particularly in smaller organizations, about how development differs between a traditional vial system and a prefilled syringe system.

This article therefore focuses less on the market drivers behind the shift to prefilled syringes and more on the practical considerations that must be understood, planned for, and executed during the transition.

PFS Systems Bring Combination Product Regulatory Complexity

The differences between vial systems and syringe systems matter because many injectable drugs have historically been commercialized in vial-and-stopper systems. In that model, the primary packaging is approved as part of the drug product. For that reason, development and compliance activities are generally centered on drug product requirements:

• 21 CFR Part 210: current good manufacturing practice requirements for manufacturing, processing, packaging, or holding drugs
• 21 CFR Part 211: current good manufacturing practice requirements for finished pharmaceuticals
• 21 CFR Part 600: general biological product requirements that may apply to biologic drug products, along with other relevant sections depending on the product

Moving to a prefilled syringe changes the regulatory pathway because the complete package-and-delivery system must be reviewed as a combination product in the U.S. The scope therefore expands beyond the drug product to include the device components that support administration. This framework is described in 21 CFR Part 4—Regulation of Combination Products.

Accounting For Drug And Device Constituent Parts

Because a prefilled syringe includes both drug and device constituent parts, the development program must address requirements from regulatory frameworks for each:

• Drug requirements: maintain compliance with applicable drug current good manufacturing practice expectations
• Device requirements: align with the Quality Management System Regulation (QMSR), including FDA medical device current good manufacturing practice requirements under 21 CFR Part 820, which now incorporates by reference ISO 13485:2016. This helps to bring these standards into closer alignment with international quality system standards
• European requirements: In 2021, EMA published its guideline on quality documentation for medicinal products used with a medical device. Under this framework, a prefilled syringe is generally treated as an integral, non-reusable product in which the medicinal product has the principal mode of action. As a result, it is evaluated as a drug-device combination product

Building Risk Management Into Product Development

The preceding regulatory context leads to the central development challenge: risk must be understood and managed from the beginning of the program. The driver behind this challenge is not only that syringe systems are more complex than vial systems but also that global regulatory bodies are adopting more science-based and risk-based requirements for industry. Because design controls apply to the prefilled syringe, risk-based planning should be integrated early rather than addressed later as a compliance exercise. In a previous article series on design controls, I outlined foundational concepts and offered implementation tips: “Design Controls For Drug Delivery Devices, Part 1: A Process Primer” and “Design Controls For Drug Delivery Devices, Part 2: A Practical Perspective.”

When the Quality Management System Regulation (QMSR) became effective in February 2026, it replaced the legacy Quality System Regulation (QSR). This change brought focus on continuous risk management throughout the product lifecycle. Since the institution of QMSR, risk-based citations by the FDA relating to product realization have nearly tripled from 5.67% to 14.32%, according to the FDA Data Dashboard (June 2026).

Key Considerations In A Risk-Based Approach

Early development should account for the needs of the intended patient population, the requirements of the therapeutic category, and the technical demands of the delivery system through the perspective of risk. This includes considering human factors, usability, applicable quality standards, and delivery performance expectations as part of the overall development strategy:

• Patient and use needs: understand how patients will use the product and what support they may require
• Human factors and usability: evaluate how the device design affects safe, effective, and reliable use
• Quality and regulatory expectations: align development activities with applicable standards and design-control requirements
• Technical delivery needs: define the comprehensive performance requirements of the syringe system

Cross-Functional Integration: Involving The Right Expertise Early

Successful execution also requires cross-functional integration from the earliest stages of the project. In many cases, this means bringing in new or different expertise and ensuring that all relevant functions are aligned to support both execution and compliance. I discussed this topic in more detail in an earlier article, “Drug Delivery Product Strategy: Aligning The Organization For Execution.” One aspect to make clear is the need for activities to all be explicitly tied back to risk decisions.

Practical Considerations For Product Developers

In addition to the compliance aspects touched on above, I want to focus on some of the practical aspects of developing a prefilled syringe system and the expanded testing and understanding that will be needed to execute effectively. Development should begin with the end state in mind, including the needs of the intended patient population and the way the product will be used in real world scenarios.

For biologic drugs, whether initially developed in vials or intended for a prefilled syringe application, a central consideration is the drug itself: its formulation, stability, and compatibility with the primary package. In a prefilled syringe system, the dual role of primary package and delivery system makes product/package compatibility, device performance, and patient interaction with the system equally important:

• Formulation and compatibility: confirm that the drug formulation remains stable and compatible with the syringe components throughout the product lifecycle.
• Human factors and usability: evaluate how patients and caregivers will handle, prepare, and administer the product
• Labeling and instructions for use: provide clear, practical guidance that supports safe and effective use

Design For Manufacturing: A Key To Production Scale-Up

Design for manufacturing is another important part of the development strategy. The program should account for scalability, supply continuity, and the additional complexity associated with syringe fill/finish operations compared with traditional vial fill/finish processes.

These are common challenges that often get under-represented as risks historically. I have seen large pharma organizations work with outside development teams to design a device with no one on the team truly responsible for understanding how the product will scale-up in production. It is very easy to make singular prototypes, but it is a much different challenge to produce in greater volumes. This becomes a perfect example of the reason why early cross-functional engagement is so important.

Examples of related risks are offered below:

• Global supply-chain reach: The assessment should consider not only the primary production sites for components, constituent parts, and services such as fill/finish, but also the broader resilience of the supply network.
• Contingency planning: Supplier and service-provider qualification should include a clear fallback strategy in case a disruption occurs at a primary site or within a critical supply path.

The Multi-Faceted Nature Of Lifecycle Management

Lifecycle management should also be planned early. The organization must define how risk will be monitored over the life of the product, how changes will be assessed and reported, and how quality or safety complaints will be managed.

Continuous risk management: Regulatory agencies and related standards increasingly reinforce that risk management is not a one-time activity. It must continue throughout the product shelf life to help ensure that products remain safe, effective, and fit for use:

• Holistic process oversight: For combination products, QMSR adds complexity by requiring organizations to evaluate processes as interconnected systems rather than as stand-alone activities.
• Supplier and partner management: Because suppliers and service providers are involved in every case, these partnerships must be actively managed and integrated into the overall risk-management approach.
• Change control: Change management, both within the organization and with external partners, should be a primary area of focus. Understanding each change and its potential impact is essential to protecting patient and user quality and safety.
• Post-market surveillance and reporting: Post-market surveillance reporting is required in both Europe and the United States. Organizations must maintain this documentation and provide it to health authorities upon request. User feedback, adverse events, and other product complaints should be routinely analyzed to identify safety signals, assess product performance, and support ongoing risk management. Applicable reporting obligations should be built into the post-market surveillance process, including expectations described in FDA guidance on Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines | FDA.

The Criticality Of Device Functional Performance

When a sterile biopharmaceutical drug is developed in a vial system, functional performance is typically a limited area of focus. The intended user population should still be understood so the final product can be designed appropriately. However, unless the vial is supplied as part of a kit or labeled for use with a device such as a vial adapter, the system is generally not treated as a combination product under U.S. FDA expectations.

That changes with a prefilled syringe system. Because the syringe serves as both the primary package and the delivery mechanism, functional performance becomes a central development consideration.

For example, ISO 11040-4:2024 identifies functionality testing that should be considered for syringe systems. Examples include:

• break-loose force
• glide force
• extrusion force
• needle pull-out force
• needle shield pull-off force

In addition to understanding the empty syringe system itself, critical work must be done with the drug products to assure aspects such as deliverable volume to the patient.

Global Standards And Requirements Guiding PFS Development

ISO 11040-8:2026 is the international standard governing requirements and testing for finished PFS. This section addresses the evaluation of the syringe as a combination product under conditions that reflect actual use. The 2026 update reflects use of deterministic test methods and the use of testing parameters that are tailored to a specific application, and it provides guidance on characterization of the empty prefilled syringe system early in development.

In Europe the PFS is considered an Integral System so the Medical Device Regulation (MDR) provides a guide for General Safety Performance Requirements (GSPRs) that must be completed and submitted for combination product approval.

All of this work is culminated in the Design Verification and Design Validation programs.

Added Complexity In Container Closure Integrity

Container closure integrity (CCI) is critical for all sterile products, whether packaged in vials or prefilled syringes. It is a useful example of how the same quality attribute can become significantly more complex when moving from a vial system to a syringe-based system.

In a vial system, the seal is created at the interface between the glass vial and the rubber stopper. Both the stopper plug and the vial flange contribute to sealing performance. When component dimensions, design features, and the crimping process are well understood and controlled, the system can typically achieve adequate closure integrity.

By contrast, a prefilled syringe introduces multiple potential leakage paths and additional variables because key components may move or respond differently under changing environmental conditions. Significant development considerations include:

• Primary leakage points: the needle shield on a glass syringe and the plunger within the syringe barrel
• Design and material factors: component dimensions, interference fit, surface morphology, coatings, and other interacting variables.
• Process and environmental factors: fill/finish conditions, syringe headspace, pressure changes during air transport, and other stressful environmental conditions

With these factors in play, CCI in a prefilled syringe requires a broader understanding of both the component and system design, as well as the manufacturing process. The testing technique may also need to be changed due to the format change, so analytical understanding provides critical support to this endeavor. The goal is to control the system in a way that maintains closure integrity throughout distribution, storage, and use throughout shelf life.

Understanding Materials: Biocompatibility, Extractables, and Leachables

Biocompatibility is another area that must be addressed when developing a combination product. For a traditional drug-container system, evaluation often focuses on extractables and leachables associated with the packaging. For a prefilled syringe, however, the device constituent introduces additional expectations under the ISO 10993 series and applicable medical device regulations. The FDA guidance "Use of International Standard ISO 10993-1, ‘Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process’" provides additional insight on how to leverage the ISO biocompatibility standard from an FDA perspective.

For drug products, standard references typically include the following:

• Product Quality Research Institute (PQRI) recommendations Leachables and Extractables – Product Quality Research Institute
• USP chapters <1663>, Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, and <1664>, Assessment of Leachables Associated with Pharmaceutical Packaging/Delivery Systems

These references support material characterization and the identification of compounds of potential safety concern. Extractables studies may use exaggerated or simulated conditions and should be interpreted with an understanding of the analytical evaluation threshold. Leachables testing is typically performed on validated drug product batches and may include both targeted and non-targeted screening, with results correlated to the components used in the system.

For a combination product, the device constituent should also be evaluated using the ISO 10993 series and applicable medical device regulatory expectations, including the European Medical Device Regulation (MDR) Regulation (EU) 2017/745 (EU MDR), where relevant.

This evaluation expands the focus beyond pharmaceutical extractables and leachables to include biological safety of the device materials. It includes these considerations:

• Material composition: characterize materials and assess potential toxicological concerns under appropriate extraction conditions
• Chemical equivalence: evaluate whether materials and chemical profiles remain consistent across device lots and clinical use conditions
• Clinical relevance: assess whether observed or potential leachables are appropriate for the intended route of administration and duration of patient contact

In May of 2026 the FDA added ISO 10993-1 (2025-11) Biological Evaluation of medical devices to its recognized consensus standards database. For the FDA this recognition is partial, however. As an example, they want biologic risk estimation to follow ISO 14971:2019 Medical Devices-Application of risk management to medical devices. Biological evaluation plans should be developed accordingly.

Fill/Finish And Process Understanding

Sterile drug and biopharmaceutical filling can be challenging in both vial and syringe formats. Vial filling is supported by decades of CDMO experience, while broader syringe fill/finish expertise has expanded more recently.

For prefilled syringes, fill/finish should be treated as a critical development activity because it directly affects the delivered dose. Unlike vials, which often include overfill to support dose withdrawal, syringes require tighter control of fill volume and related process variables to ensure accurate dose delivery. Critical process parameters (CPPs) should be identified during development and carried out through the technology transfer program to ensure the process is well understood, controlled, and scalable.

Several process and system variables can directly affect the delivered dose and overall performance of the final combination product, including:

• Fill volume: confirm that the filled quantity supports the intended deliverable volume
• Headspace: understand how air volume and compression may affect dose delivery and system behavior
• Residual volume: account for drug that may remain in the syringe after administration
• Process interactions: evaluate how fill/finish conditions, component selection, and system design influence final product performance

Organizational Implications Of A Vial-To-PFS Transition

The decision to move to a prefilled syringe can provide meaningful benefits, but it also changes the regulatory strategy and development pathway. Organizations, whether emerging biotech companies or large pharmaceutical companies, should expect a longer development cycle and the need for additional expertise to support the transition.