Mechanical Robustness of 2R Glass Vials Across Fill/Finish Operations: Implications for Biopharma Manufacturing

Strategies to optimize the fill/finish stage of biopharmaceutical manufacturing and to reduce risk are receiving growing attention. In this stage, the drug product is transferred into its final container, such as a vial, syringe, or cartridge, before sealing and labeling.

Historically seen as a relatively straightforward phase following laborious drug development, fill/finish has evolved into a complex and multifaceted process in its own right.¹ Sensitive biologics, high-volume and high-viscosity formulations, and the trend toward personalized medicines have introduced further challenges. As a result, fill/finish demands greater precision, control, and container performance than ever before.

The stakes are high, as errors lead to costly delays and batch rejections. In 2023, the Tufts Center for the Study of Drug Development ran a study to quantify the impact of delays, concluding that a single day of delay costs approximately $800,000 in lost prescription drug or biologic sales.²

“The fill and finish step is the final and one of the most critical stages of the production process, where the drug product—often a sterile liquid—is transferred into its final container, such as a vial, syringe, or cartridge. For lyophilized drugs, the liquid is filled into the container and then freeze-dried in place. This step must be carried out under highly controlled and sterile conditions to ensure the product remains uncontaminated and safe for patient use. Once filled, the containers are sealed, labeled, and packaged, completing the product’s journey from formulation to distribution,” according to Vine (2025).³

Why does every vial count?

In biopharma manufacturing, high-value drugs are processed at increasing line speeds. High-speed filling lines, for instance, achieve a throughput of up to 600 vials per minute for vials containing liquid or freeze-dried products, starting from washed and depyrogenated bulk containers.⁴ At such rapid production rates, it becomes critical to ensure the integrity of every vial moving along the line.

Glass remains the optimal material for biopharma packaging, thanks to its “hermeticity, transparency, strength, and chemical durability”.⁵ However, during handling and processing, in which containers undergo repeated impacts at varying intensities, glass is vulnerable to damage. Breakage during filling leads to line stoppages, production downtime, material waste, and loss of valuable drug product. More importantly, it may compromise the sterility or overall safety of the medicine.

For these reasons, robust mechanical integrity, recognized as the ability of a container or packaging component to maintain its physical strength and protective function, plays a decisive role in operational efficiency and product safety. In a high-speed, high-value manufacturing environment, every vial truly counts.

Breakage and contamination control

“Contamination Control Strategy (CCS)—A planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control,” according to the European Commission.⁶

There are regulatory implications, too. The revised European Union (EU) good manufacturing practice (GMP) Annex 1, which focuses on the manufacturing of sterile medicinal products and came into force as of 2023, places greater responsibility on biopharma companies to ensure robust contamination control.⁶

The revision stipulates, “A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks to medicinal product quality and safety.”⁶

It also clarifies that, “The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g., pyrogen, endotoxin) as well as particulate (e.g., glass and other visible and sub-visible particles).”⁶

In this context, the mechanical robustness of glass vials is directly linked to contamination control; breakage introduces particulate contamination risks, disrupts aseptic conditions, and challenges compliance with Annex 1 expectations.

Where is breakage most likely to occur?

The onus is on biopharma companies, as well as partners and suppliers, to ensure thorough testing of glass vials. Assessing the journey of a vial through the fill/finish process helps identify where breakages are most likely to occur, as well as the most sensitive parts of the vial. With this insight, manufacturers can take informed remedial action and achieve compliance with confidence.

To support drug developers and manufacturers in this effort, and to demonstrate practical methods for assessing mechanical integrity, the authors conducted a comparative study of 2 types of 2R vials (2R indicates dimensions defined by ISO 8362-1).

As the 2 vial categories differ in quality specifications and secondary packaging configurations (i.e., with or without glass‑to‑glass contact), the study examined their mechanical resistance at multiple processing stages.

Study design

Simulating a fill/finish process to compare breakage and visual defects

Objectives. The aim of the study was to assess and compare how each step in the fill/finish process affects the mechanical strength and the cosmetic appearance of 2 distinct 2R vials, and to quantify the contribution of each step to overall vial integrity.

Vial descriptions. The first bulk vial (Fina, Stevanato Group) is well suited to a variety of end markets/applications, aligning with market standards in cosmetic and mechanical quality. The manufacturing process is characterized by high stability and repeatability across multiple plants, but entails glass-to-glass contact through forming as well as the final packaging.

The second vial (Nexa, Stevanato Group) is recommended for high-value drugs such as biologics. No glass-to-glass contact occurs during the production and packaging of this vial. The manufacturing line is equipped with an advanced set of automatic cameras that detect smaller defects and operate under stricter acceptance criteria.

Testing conditions. Two different fill/finish runs were simulated with different equipment and manufacturers.

To assess mechanical integrity, one of the fill/finish simulations was conducted in collaboration with Syntegon, a packaging machinery manufacturer and technology partner, at its premises in Crailsheim, Germany. In this setup, the authors performed the final testing of the vials to characterize mechanical performance.

The other simulation was carried out with IMA Group, a manufacturer of automatic processing equipment. In this setup, the authors added an automated visual inspection at its own site in Piombino Dese, Italy, to identify defects that would result in vial rejection (i.e., to assess cosmetic quality). An offline, post– fill/finish vision system was used for the inspection.

Tests conducted. Burst pressure and vertical compression tests were carried out after each fill/finish step to assess mechanical resistance (see Figure 1).

Fill/finish simulation at Syntegon

A batch of vials of both categories (i.e., Fina and Nexa) were shipped from Stevanato Group to Syntegon’s site using the original secondary packaging (with glass-to-glass contact in the case of Fina and without for Nexa). Following a fill/finish run, performed at a speed of 412 pieces/minute, all vials were returned to Stevanato Group using secondary packaging with an alveolar separator, eliminating glass-to-glass contact and thereby minimizing the risk of impact during transport.

The simulation steps were as follows:

• Step 1. Infeed and washing (50 pieces were tested from each batch)
• Step 2. Depyrogenation and rotary table (50 pcs)
• Step 3. Filling (using water) and stoppering (50 pcs)
• Step 4. Capping and crimping (100 pcs).

For each category, the vials were subjected to burst test and vertical compression to identify how each step impacts vial performance.

Burst test results: maximum internal pressure

The Nexa vials demonstrated consistently higher median Pmax values, and, therefore, higher inherent mechanical strength, than the Fina vials at every stage of the process (see Figure 2). Across the Nexa workflow, Pmax showed an average decline of approximately 14% from the bulk manufacturing stage (i.e., the vial manufacturing process) to Step 4 (capping and crimping).

Fina vials began with lower initial strength than Nexa; however, the subsequent steps did not appear to cause substantial additional loss in mean Pmax. For both vial types, overall variability in mechanical strength likely reflects differences between batches and the specific boxes sampled within each batch.

Burst test results: fracture origin

Following each burst test, the testing team examined where failures tend to originate on the vial surface, where the fracture started, and how it spread (see Figure 3). When tested immediately after manufacturing, many of the Fina vials fractured at the shoulder and heel. The shoulder (the curved upper part of the vial body) and the heel (the curved bottom edge) are structurally sensitive areas in glass vials. After Step 1 (infeed and washing), the failure percentages in these areas decreased, while failures originating from the body increased.

In contrast, the Nexa vials showed a high percentage of bottom fracture origin when tested directly after manufacturing. Following Step 1, the proportion of failures beginning in the body also increased. Both Fina and Nexa vials showed an increased fracture origin percentage on the body throughout the process steps, which might be attributable to glass-to-glass and glass-to-metal contact.

What were the vertical compression results?

As in the burst testing, the Fina vials began with lower initial mechanical strength than the Nexa vials, but the subsequent steps did not lead to a substantial further reduction in mean Fmax.

In contrast, the Fmax of the Nexa vials decreased as they progressed through the fill/finish processes. In particular, Step 1 had the most profound impact on mechanical resistance, with a 45% reduction of the mean Fmax compared to the bulk manufacturing step. Nonetheless, Nexa’s mechanical resistance remained superior to Fina at each phase of the stimulation (see Figure 4).

Cosmetic rejection rates following fill/finish at IMA Group

The fill/finish process at IMA Group followed a slightly different sequence:

• Step 1. Washing and depyrogenation
• Step 2. Filling (1.2 mL of water), stoppering, and crimping.

The vials were tested at 2 line speeds, 150 pieces/minute and 400 pieces/minute, and subjected to both burst test and vertical compression. Next, Stevanato Group ran an automated visual inspection at its specialist Optrel site at 400 pieces/minute.

This inspection provided additional insight into defect formation and detectability. Detected defects were primarily fine airlines, scratches, and black scratches. Original data showed a high frequency of body‑initiated flaws, meaning that stresses or surface defects located on the main sidewall of the vial can propagate into cracks or fractures when exposed to mechanical forces. This finding aligns with fracture origin trends observed in the mechanical tests.

The cosmetic rejection rate, referring to the percentage of vials rejected due to visible defects, was more than 2.5% lower for Nexa vials (see Figure 5). This superior cosmetic quality is most likely attributable to the absence of glass-to-glass contact during forming and packaging, as well as the use of an enhanced inspection system during production.

Discussion

In this study, Stevanato Group leveraged its network of partners in biopharma machinery and manufacturing to deepen understanding of vial performance during fill/finish.

The study identified the washing and depyrogenation stages as the most impactful on mechanical degradation, causing measurable reductions in mechanical resistance. These steps introduce significant stress and mechanical loading, which can generate or enlarge microdefects.

Even when using higher quality vials, such as Nexa, fill/finish degrades mechanical resistance after bulk manufacturing. Reducing glass-to-glass or metal-to-glass contact is therefore advisable.

Nonetheless, at each measured stage, advanced-quality vials consistently show a higher mechanical resistance. This characteristic implies that a higher quality vial at baseline translates into better or similar mechanical performance both before and after the fill/finish process. Ultimately, this attribute reduces defect rates and minimizes the number of vials rejected during processing.

Integrating mechanical and visual inspection data demonstrates that process-induced stresses affect not only mechanical resistance but also cosmetic integrity. These findings reinforce the need to evaluate vial robustness holistically across fill/finish operations to support reliable biologics manufacturing and minimize the risk of process deviations.

Given the scale of biopharma manufacturing, this initial investment is invaluable. It helps quantify the extent to which manufacturing stresses compromise vial strength, supports reduced failure and rejection rates, and minimizes avoidable downtime. The more thoroughly that manufacturers understand the mechanical integrity of glass containers, the more effectively they can control this parameter, and the easier it will be to meet evolving regulatory expectations and ensure consistent product quality.

About the authors

Riccardo Prete is a product manager and Arianna Melchiori is a product specialist at Vial Platform, Stevanato Group. Dario Zagallo is SME Study Monitor—EMEA Technology Excellence Center (TEC) Analytics at Stevanato Group.

References

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