INTRODUCTION

The biological drug market continues to grow due to a robust and steady pipeline of product innovation. Eighteen biologics were approved by the US Food and Drug Administration (FDA) in 2024 compared with just 12 in 2021.^1,2

Biologics are typically administered via injection due to two key factors: their large molecular size, which can hinder bioavail­ability and make oral or inhalation formulation difficult, and their sensitivity to degradation in the gastrointestinal (GI) tract if taken orally. Consequently, these biologics must be manufactured, filled, and finished in a sterile environment adhering to Annex 1 of the EU Good Manufacturing Practice (GMP).

The growth of the biologics sector has led to the diversifica­tion of alternative container formats for injectable products be­yond the standard vial. It is vital that pharmaceutical companies select the most appropriate format to achieve the target product profile (TPP), as each format has features and benefits that make it suitable for different therapies and use cases. Careful consid­eration of drug product and end-patient needs, as well as sterile integrity requirements, is needed in this selection process.

The following explores the importance of container selection for sterile injectable drug products and outlines key factors to con­sider to optimize the performance, quality, and efficacy of bio­logics.

THE IMPORTANCE & CHALLENGES OF CONTAINER SELECTION

The complexity of the protein structures within biological ac­tives means meticulous consideration of fill form is particularly vital. Unlike small-molecule pharmaceuticals, biologics are highly susceptible to degradation from external factors, making con­tainer selection a critical determinant of product safety and effi­cacy. The primary container is a protective shield, doing more than just ensuring patient safety by preventing microbial and for­eign body contamination. It also helps maintain the drug’s in­tegrity throughout its shelf- life.

However, the interactions between these complex drug for­mulations and their containers present unique challenges during sterile fill and finish. Key considerations include:

Material compatibility: Biologics can interact with container ma­terials, leading to leaching of chemicals, which can compromise drug stability or induce adverse patient reactions. Oxidative stress can also occur during storage, which can lead to premature degradation of the formulation within. To maximize shelf-life and ensure the packaging is compatible with the formulation, it is es­sential to conduct sufficient extractables and leachables testing of both the container and closure in the early stages of develop­ment.

Viscosity and delivery: High-concentration biologics often exhibit high viscosity, demanding precise fill volumes and consistent delivery forces. Container design must ac­commodate these properties to ensure ac­curate dosing. This is especially important in self-administration devices, where pa­tients must be able to reliably inject the medication.

Meeting sterile fill & finish needs: The container must be able to support sterile integrity during and after the filling process. Flawless container closure in­tegrity is needed to prevent microbial con­tamination. The containers must also be capable of withstanding terminal steriliza­tion processes, if such a step is needed, without degrading.

Container closure integrity: Maintaining container closure integrity is especially dif­ficult when considering the extreme tem­perature ranges that some biologics must be stored within.

In addition to these challenges, biophar­maceutical companies must consider other issues. Human factors, such as patient ex­perience and convenience, play an impor­tant role in container selection. If a product is to be self-administered, for example, then the container should be able to sup­port easy administration by the patient, without the need for professional training. Logistics considerations, such as transport and storage, should also be taken into ac­count during container selection, to ensure the final choice meets the needs of the drug product.

CHOICE OF FILL FORM

A number of presentations are now available for biologics, including:

Vials: Well-established, these are simple, small vessels made of glass or plastic with a metal or plastic closure to seal the prod­uct inside.

Pre-filled syringes (PFS): Containing a single dose of medication, PFS streamline the administration process, minimizing the risk of dosage errors and reducing med­ication waste. This method also has the potential to enable self-administration of a wider range of treatments, leading to in­creased accessibility and convenience for patients.

Blow-fill-seal (BFS): This is a sterile man­ufacturing process that forms, fills, and seals lightweight plastic containers in a single, continuous operation. This process is ideal for single-dose applications, as it enhances self-administration, reduces product waste, and streamlines production and transportation costs.

Alternative administration routes: Alter­native delivery routes to injectables are also available for a range of biologics therapeutics due to innovation in formula­tion technology and administration de­vices. Inhalation in particular offers advantages in terms of ease of adminis­tration and enhanced patient comfort, which makes it highly attractive for the lo­calized treatment of chronic pulmonary diseases, where patient compliance is cru­cial to the successful management of the condition.

When selecting the most appropriate fill form for biologic drug development projects in which injection is the chosen format, several priorities must be consid­ered. These priorities will vary depending on the stage of drug development, as the requirements for a Phase 1 clinical trial therapy differ significantly from those for a commercialized treatment.

The decision on fill form should not be delayed until Phase 3. Instead, it should be made and agreed upon early in the de­velopment process. This proactive ap­proach ensures that measures are in place to facilitate the smooth transition of the therapy into clinical trials and commercial­isation.

FACTORS TO CONSIDER DURING SELECTION

The unique features and benefits of each container format (whether it is new to the market or has been around for a long time) will influence the selection process. The specific biological therapy, desired product profile, and patient needs will determine the best format.

The benefits and key considerations of the most important formats impacting on the injectable market include:

Vials: These are readily available and have well-established production infra­structure, making them a cost-effective and easy option with quick speed-to-mar­ket. Suitable for various biologic formula­tions, they are ideal for Phase 1-3 clinical trials. Additionally, they can hold multiple doses, which decreases filling and trans­portation costs. When choosing a vial for a project, consider the development stage and whether a multi-dose container would be better than a single-dose container. If so, vials may be the ideal choice.

PFS: Offer significant advantages, im­proved dosing accuracy, and minimized waste. These benefits are achieved by pro­viding a single, pre-measured dose, thereby reducing microbial contamination risk because reconstitution is needed and ensuring patients receive the correct amount of medication. The ease of self-administration also improves patient con­venience. As a result, PFS are particularly valuable for high-value products in which waste reduction is essential and for com­mercialized products treating chronic con­ditions, as they enhance usability.

BFS: These provide numerous advantages, including reduced risk of breakage and contamination, elimination of preserva­tives, improved dosing accuracy, and min­imized drug waste. These benefits are due to the plastic composition, single-dose fea­ture, and immediate sealing after filling. BFS is suitable for ophthalmic and in­jectable biologic projects, high-value drug formulations, and high-volume commer­cial filling, due to innovations in the process and efficiency advantages.

OTHER CONSIDERATIONS TO BEAR IN MIND FOR BIOLOGICS

Temperature control is frequently a key requirement to guarantee biologics reach the patient in good condition and remain stable when stored for long peri­ods. This means the formulations must be kept at fresh, frozen, or even ultra-frozen temperatures during both transit and stor­age. Due to the need for specialist storage and transport infrastructure, temperature control creates logistical challenges. This can be a problem for products that are shipped across international borders, to emerging markets, and to remote loca­tions where cold-chain resources are not readily available.

When suitable, this issue can be ad­dressed by incorporating lyophilization into the formulation’s manufacturing process. Lyophilization freeze-dries a so­lution under a vacuum and dries the re­sulting product into a powder that is more stable at more moderate, non-cryogenic temperatures. As lyophilization impacts other choices like container selection, it has to be built into the manufacturing process to maintain optimum manufactur­ing output and efficiency.

EXPERT GUIDANCE NEEDED

Getting container selection right at the earliest phase of drug development is vital to ensuring the overall success and prof­itability of the project, and to delivering a truly life-transforming treatment for pa­tients.

A contract development and manu­facturing organization (CDMO) partner with specialist experience in sterile fill and finish of an array of injectable container formats can support biopharmaceutical companies in understanding the fill form needs of their biologics. They can help se­lect the most effective presentation to fit their product’s TPP, addressing human fac­tors, transport and storage needs.

With such support, biopharmaceutical companies can have peace of mind that they have the information they need to make an informed decision to optimise the performance of their therapy.

FUTURE CHALLENGES FOR BIOLOGICS FILLING

The steady introduction of new drugs by the CDER over the past 2 decades has created a marketplace with increased competition and a need for product differ­entiation.3 This creates both opportunities and challenges for biopharmaceutical companies, which will need to develop less invasive and more convenient methods of drug administration to improve patient ac­cess and compliance.

The biopharmaceutical industry has seen a shift towardd subcutaneous (SC) in­jection, particularly for monoclonal anti­bodies (mAbs), as opposed to intravenous (IV) administration. SC offers differentia­tion opportunities and improved patient access and compliance, responding effec­tively to challenges associated with bio­therapeutics. SC drug delivery, using existing formulation and device technolo­gies, allows patients to self-administer therapies at home, rather than going to a clinic for professional administration. Con­venience for patients is enhanced, reduc­ing the burden on healthcare systems.

Further formulation advancements, such as the development of fluid suspen­sion in non-aqueous vehicles and new buffering agents to improve protein stabil­ity in aqueous solutions, will enable SC de­livery for more biological treatments over the coming years.

READY TO FACE THE FUTURE

For the biopharmaceutical sector, the choice of primary container will continue to have enormous importance for the suc­cess of a new therapy. The ideal container will improve the efficiency of the sterile fill and finish process by minimising waste and energy consumption while optimizing sterile integrity. It will also support ease of use and convenience for patients, with ad­ditional implications for logistics and stor­age of finished products.

Therefore, it is crucial to work with ex­pert sterile fill and finish partners to identify the appropriate container for the finished biologic and ensure commercial success. Biopharmaceutical companies can be con­fident that specialist CDMOs will provide the guidance they need to make the right container selection.

REFERENCES

1. https://www.sciencedirect.com/science/ article/abs/pii/S0223523425000066#:~:text=of_new_drugs.-,Abstract,18_biological_entities_(NBEs).
2. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC10856271/#:~:text=In_addition%2C_the_Cen­ter_for,A%2C_B%2C_C%2C_W.
3. https://www.researchgate.net/publication/ 338865718_Trends_in_FDA_drug_

Vincenza Pironti is the current Head of Business Development at Recipharm, having joined the company in 2023 as Strategic Marketing Director for Sterile Fill and Finish. She supports the design of strategies for the global sales and business development teams, and the analysis of new business opportunities for Recipharm’s commercial business. With almost 20 years in the pharmaceutical industry and consolidated experience in business development, product development, aseptic manufacturing, and filling, she brings valuable expertise to Recipharm. She comes to the business with extensive knowledge of all phases of product development, from formulation screenings to sterile product commercial manufacturing, with expertise in small molecules and biologics in sterile formulation. Previously, she worked as Business Development Manager in Pharmatex and CordenPharma, managing multiple projects in sterile fields.