Enhancements in glass pre-fillable syringe manufacturing

Nowadays, it is possible to overcome most of the limitations that still prevail on glass PF-syringes, thanks to an innovative engineering approach, combining high quality glass forming with pioneering features. Paolo Golfetto, R&D Manager, Glass Division, Stevanato Group, provides an outlook on incorporating improved technical features in glass pre-fillable (PF) syringe manufacturing

Glass syringes are the primary packaging of choice for drugs and vaccines in the US and European pharmaceutical markets. Quality requirements for primary packaging are steadily increasing following FDA recommendations to reduce any risk of failures and to insure functional performance with the latest generations of delivery devices and safety devices. Fulfilment of these new requirements is only possible by combining expertise on glass forming with a new designing and engineering approach for development of innovative process.

Stevanato Group, by combining the design capabilities of its engineering division with the long experience in the production of superior quality glass containers for pharma packaging, designed and developed fully re-engineered glass syringe manufacturing equipment with implementation of highly efficient devices and innovative solutions. Application of these solutions to mass market products led to the development of improved glass syringes that give a broad range of benefits for pharma companies and innovative features for the final users.

PFS challenges
Pre-filled syringes (PFS) constitute one of the fastest growing markets in the drug delivery and packaging sectors, with estimated global production of 2.4 billion in 2010. Several studies predict this growth to continue in the next years and the ready-to-use format is gaining more and more standard solutions such us EZ-fill in nest/tub configuration.

Fig. 1 ISO 11040 design and critical areas under stress by using autoinjectors or safety devices

The standard requirements for syringes manufacturing are well fixed by ISO 11040 and the 1 ml long format has become the most common configuration for biotech products. Nowadays, quality expectations for syringes are growing at a rapid rate especially linked to safety and convenience for patients. Pharma companies and regulatory agencies are pushing suppliers to reduce defects and at the same time to improve syringe performance in combination with drug delivery devices. (see Fig 1)

The growing demand in the market for safety systems and autoinjectors due to recent legislation and to the final user request is highlighting the critical aspect of interaction between glass syringes and metal and plastic components. To analyse this aspect, Ompi decide to put in place a study starting from two well know safety system and autoinjectors suppliers. Attaching devices or backstops can utilise the flange, often snapped onto finger flanges. Moreover, self-injection systems such as spring driven-driven autoinjectors that incorporate pre-filled glass barrels lead to high pressures and forces on the primary packaging. Often the internal configuration is adapted to the proper syringe formation.

By this method we determined the complete settings of the relevant critical design of the primary packaging where there is a gap between  the nominal values and the optimal one. (see Fig 2)

Fig. 2 Standard syringe design requirements and Ompi syringe improved tolerance

The Stevanato Group consists of the glass division that manufactures glass containers from tubing glass with Nuova Ompi being the largest part and the engineering division that design and build machines for the production and quality control of containers from tubing glass and consists of SPAMI and Optrel companies. Thanks to the synergic combination of expertise of the glass and engineering divisions, within Stevanato Group all the converting process is under control. Syringe assembly machinery are being optimised with innovative proprietary solutions to achieve the finest quality production.

Process
Manufacturing syringes glass barrels can be described as placing in vertical position the glass tubing, cutting Type I borosilicate glass cane to the desired length, heating both ends and forming the cone and flange, annealing, inserting a staked needle if required, washing and siliconising.

The first critical step is the barrel forming process. At Nuova Ompi this is performed by the latest generation of machines from SPAMI that are designed to continuously monitor the glass temperatures during the cone and flange forming process. In addition, flow meters are used to keep under control the gas mixture of the burners. This precise temperature control together with the components being held and moved by specialised grippers and high precision servo motors combine to produce barrels with tight dimensional tolerances and reduced critical defects. Cone tip forming and flange forming are performed reaching an accurate overall length thanks to recalibration action (see Fig 3)

Fig. 3 Total length control technology applied to the glass syringe barrel

To reduce circular runout we introduced a new generation of holding chucks, key tools of an autocentering system obtaining a very high centricity and a high precision degree.

After forming, the barrels undergo 100 per cent dimensional inspection by the Novis camera system, which is an internal development of SPAMI with special attention being given to the critical area of syringe cone. (see Fig. 4)

Fig. 4 100 per cent camera controls performed inline by Novis technology and best results obtained thanks to new technology applied

Due to the stress that could be placed onto the flanges by safety systems and autoinjectors, we performed a study on the flange mechanical resistance with a mathematical analysis study of variables leading to reduced performances. (see Fig 5)

Fig. 5 Flange stress test results performed by R&D department in order to define flange resistance improvements

Results suggest that the use of a reduced radius round flange could have the best mechanical resistance.

New inspection technology developed by Optrel controls the geometry according to the new requirements checking especially for last generation of safety devices and autoinjectors:

• orthogonal deviation (flange robustness, syringe handling and  assembling operations)
• window fit (based on customer specs)
• bending (flange geometry)
• body deformation (design compliance)

The barrels then enter the lehr tunnel for clean annealing phase, an important process that removes the internal strains developed in the glass during the forming process. Special technological applications allow a strong reduction in particle contamination. Temperature monitors are placed at multiple points in the tunnel to accurately control the thermal cycle to ensure reproducible results. Following the lehr, additional cosmetic inspections are performed in a cleanroom prior to the next steps in the process. All manufacturing phases are glass-to-glass contact free thanks to the state-of-the-art handling systems in order to avoid any possible critical and cosmetic defects generated by the process. (see Fig 6)

Fig. 6 No glass-to-glass contact during the handling systems

The last area investigated by Ompi R&D team has been the one identified as ‘Extractable’. It has become more and more relevant in the last five years related to potential interactions between sensitive molecules (especially biotech formulation) and primary packaging.

Three main concerns evaluated:

• Tungsten residuals
• Needle assembly (adhesive)
• Silicone quantity and distribution

Tungsten is introduced into the syringe, during the forming process, from the pin used to create the internal channel on the barrel tip. This material is used because of the good combination between resistance to high temperatures and mechanical properties. The sudden change of temperature in the pin is responsible of two sources of contaminations. These are

• Part of the Tungsten vaporises at high temperature and deposit in the funnel area as it reaches the ‘cold’ glass
• Part of the Tungsten oxidises between 800 and 900 °C, this oxide reacts at about 1200 °C with Sodium Oxide Na2O that emerges on the surface from the glass structure forming SodiumTungstate (Na2WO4). It has been demonstrated that high level of temperature generates migration of substances to the glass surface and some biotech molecules can interact forming undesirable protein aggregations.

Ompi established a new way of processing the cone tip forming,  dramatically reducing the level of tungsten residuals through optimised control of key process parameters.

There are nowadays three different families of syringes:

Standard process: Syringes produced with tungsten tools, the extractable tungsten level is low and compatible with most of the drugs/proteins today in development.
Low tungsten process: Syringes produced with tungsten tools and optimised processes, the extractable tungsten level is very low and compatible with very sensitive drugs/proteins
Tungsten-free process: Syringes produced with tools not containing tungsten, no extractable Tungsten is present. The only critical issue is related to high cost of alternative tools. (see Fig 7)

Fig. 7 Standard vs low tungsten process results

Needle insertion for staked needle products can now be performed using customised high-speed assembly units operating in the clean room, which include 100 per cent automated inspection for total height with needle, needle axially, needle tip deformation, clogged needles and adhesive distribution.

Complete polymerisation of the glue is assured not only checking the adhesion property of the adhesive but also having verified the cohesion property by introducing specific HPLC test to affirm the highest possible conversion rate. This important result has been obtained by validating an improved UV curing process including innovative UV irradiators and specific irradiation geometries.

Advances in drug formulation have allowed more biodrugs to be delivered in a liquid stable form, reducing the requirement for lyophilisation. The liquid stable form can then be packaged in a PF syringe, without passing through the lyo-vial phase, reducing time to market

As more and more biomolecules are packaged in PFS systems, the issue of sensitivity to silicone becomes important, also linked to the nature of the Drug Product Vehicle, which may contain substances such as surfactants, which can increase the degree of silicone extraction from the glass surface.

This new trend is requesting enhanced biocompatibility decreasing  the quantity applied on the glass barrel, the distribution and the silicone droplets dimensions.

Decreasing amount of silicone oil and new distribution patterns are direcly related to two aspects in conflict:

• Gliding performances (high silicone oil quantity)
• Low extractable silicone profile (low silicone oil quantity)

In order to understand limits and potential improvements of existing process based on diving nozzles, Ompi R&D decided to test:

• Syringe production with differentiated areas where silicone can be distributed;
• Evaluation of the correlation between silicone aggregation and sprayed droplet size;
• Several microscopic detection technologies available in the market in order to monitor the benefits potentially obtained on syringesiii

The full automation of our pre-fillable syringe production lines provides several parameters that can be fine tuned in order to set the silicone oil deposition profile.

Starting from these parameters we conducted a design of experiment (DOE) study focused on determining the different families of syringes based on varying the process parameters.

One important aspect to reduce the interaction between biodrugs and silicone and consequently the risk of protein-silicone aggregation is the dimension of silicone droplets applied on the glass surface.

Thanks to the research conducted we were able to identify several potential silicone profiles with a new silicone atomisation based on reducing the overall dimension of silicone droplets.

A key phase in the process was setting the air pressure and the air activation to have a better atomisation and smaller silicone droplets.

Through this reduced droplet size we achieved a significant reduction in quantity of silicone oil used and an optimised surface coating without jeopardising the gliding force performance
expected.

Previous silicone profile	New silicone distribution profile
Fig. 8 Distribution profiles with different droplet sizes (ZEBRA-SCI Images)

Tests have been conducted using a ZebraSci Instrument system in order to verify distribution profiles and droplets size results. The reduction of sub-visible particles in prefilled syringes manufactured by Ompi has been registered at customer’s site confirming as hypothesised at the beginning of the study, the existing direct relationship between the optimisation of distribution and droplet size (see Figs 8-9)

Fig. 9 New silicone distribution model based on small droplet paradigm

Conclusion
Only integrating expertise on glass forming with a new design and engineering approach for development of innovative process allows overcoming most of the limitations nowadays still present on glass PF-syringes. Stevanato Group, by combining the design capabilities of its engineering division with the long experience in the production of superior quality glass containers for pharma packaging, designs and develops a fully re-engineered glass syringes manufacturing equipment with implementation of highly efficient devices and innovative solutions. This uniqueness allows achieving relevant developments of improved glass syringes that give a broad range of benefits for pharma companies and innovative features for the final users.

References
Prefilled Syringes and Related Systems: World Market Outlook201-2025 – Visiongain (2010)
Prefilled syringes: Drugs, Devices and Disease Therapeutics, Greystone associates, (2009)
 “Promoting Dosing Accurancy with Prefilled Syringes” D. Vaczek PMP April 2007
“Pre-fillable Drug Delivery Offerings are the container of choice for Parenteral Drug Formulations” T. Schoenknecht, PDA The Universe of Pre-filled Syringes, 2009
 “Fine tuning of Process Parameters for Improving Biocompatibility of Prefilla-ble Syringes”, A. Sardella, ODD, (2010)