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Autumn 2008
PREFILLED SYRINGES:
THE CONTAINER OF CHOICE FOR TODAY’S INJECTABLES

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CONTENTS:

The rise of prefilled syringes from niche product to primary container of choice: a short history
Mathias Romacker, Dr Thomas Schoenknecht
& Dr Ronald Forster
Amgen Inc

EZ-Fill: Offering A New Choice In Glass Pre-Fillable Syringes
Dr Michael N. Eakins
Eakins & Associates

Stelmi Rigid Needle Shield: The Successful Concept With The Anti Pop-Off Patented Design
Jean-Pierre Merceille
Stelmi S.A.
Current considerations and future directions for E-beam sterilisation in the prefilled
syringes market: an overview

By Guy Furness
Company profile
Hyaluron Contract Manufacturing (HCM)
The next generation of ready-to-use prefillable syringes: first in silicone-free solutions Bernie Lahendro
West Pharmaceutical Services

Understanding the complexities involved in manufacturing and meeting customer’s expectations in delivering prefillable syringes
Mr Harsh Shandilya
Sewa Medicals Limited

New Technologies for the Processing of Syringe Nests
Klaus Ullherr
Robert Bosch GmbH Packaging Technology

New Market Insight into Prefilled Syringes and Closure Systems: Primary Data from Patients, Nurses, Physicians and Industry Experts
Dr Arno Fries and Burkhard Lingenberg
Gerresheimer AG

Dr Arno Fries and Burkhard Lingenberg
Dr Arno Fries and Burkhard Lingenberg
Gerresheimer AG

THE RISE OF PREFILLED SYRINGES FROM NICHE PRODUCT TO PRIMARY CONTAINER OF CHOICE: A SHORT HISTORY

Demographics in developed countries suggest that aging societies will see an increased usage of pharmaceuticals.
Many of the innovative products will be large molecules like monoclonal antibodies, proteins and peptides which, for the foreseeable future, will all need to be delivered via the parenteral route.

Prefilled syringes are now the primary container of choice for most parenteral drug delivery systems. This is due to a number of factors – chief amongst them the greater medication safety and increased convenience from using a prefillable device. Alternatives, like a vial and syringe combination, require several procedures in preparation for the entire injection of the drug.
Today the global market for prefillable syringes comprises more than 2.2 billion syringes; over half are produced as sterile versions, ready to be filled without further activities prior to filling. The rest are supplied as so-called bulk syringes, where washing, siliconisation and assembly with rubber parts have to be performed close to filling.

The origins of the prefilled syringe’s rise as the preferred container were in the extremely successful market introduction of syringes as the drug delivery unit for heparins by Sanofi and Rhône Poulenc-Rorer (both now Sanofi-Aventis) in Europe in the early 1980s. Prior to this, prefillable syringes were seen as relatively insignificant niche market products. The following years saw demand for prefillable syringes explode, and they were soon used in all major therapeutic classes for injectable drug formulations.

The breakthrough was achieved mainly by the clear advantages prefilled syringes have over traditional vials and ampoules, as the use of a prefilled syringe often involves nothing more than removing the syringe from the package and performing the injection.

Together with the low overfill required for prefilled syringes compared to a classical vial, new markets in the biotech area were explored by the prefilled syringe. Over the last few years the main market for prefillable syringes opened up from Europe and spreading towards the US and Asia; both of the latter two up until recently being typical vial-based drug container markets.

During the 1990s and early 2000s the prefilled syringe had become the primary drug delivery container. However, new challenges were raised, including broadening their field of application to biotechnology and new safety regulations.

A number of other changes and new or different requirements have impacted on the prefilled syringe market over the past few years. We have seen a steady increase in the technical requirements on the (to-date) usually glass-based delivery container platform.

Break resistance and tighter tolerances for finger flanges and glass cone dimensions have changed the quality requirements for syringes. In addition more complex formulations and protein-based active substances challenged the common syringe production technology to increase process control for key production steps and implement substantial improvements in production technology.

SOLUTIONS & ALTERNATIVES FOR SILICONE & TUNGSTEN

Siliconisation of the glass barrel is one of the key process steps, as silicone is the lubricant required to allow movement of the rubber plunger through the syringe forcing the drug out of the container to finalise the injection. Protein molecules can interact with silicone and therefore the amount of silicone sprayed into the barrel has to be controlled. A balance must be struck in order to generate reasonable gliding characteristics while retaining product stability.

A number of syringe system solutions have been developed either to reduce the silicone amount significantly or to eliminate it. Low silicone systems can be achieved either by baking the silicone after application or by using a reactive silicone system applied as liquid and then being polymerised.

Baking the silicone – which requires heating the siliconised syringe at a specific temperature for an appropriate time – results in substantial stabilisation of silicone-sensitive drug formulations, as presented during the November 2007 PDA conference on prefillable syringes and injection devices in Berlin.
But it is not only the amount of silicone sprayed into the barrel which can create issues with drug stability.

The distribution of the silicone inside the syringe should be homogeneous and uniform to generate a smooth sliding profile for the plunger stopper.

This is of particular importance when syringes are combined with auto-injection devices and the administration of the drug is not done by manual injection controlled by a human hand.

Another point to be considered is the known tungsten sensitivity of some protein molecules. Manufacturers have developed several ways to reduce or eliminate tungsten as a product contact material. For glass syringes, manufacturers have introduced alternative materials to replace tungsten as heat resistant material in key glass forming process steps. Such technology is now standard and available to stabilise sensitive proteins.

Tungsten residuals together with silicone issues can be removed by using new innovative primary containers made from cyclo olefin copolymer (COC) or cyclo-olefin polymer (COP).

One manufacturer has developed such a system which is free of silicone due to full fluoropolymer film lamination of the syringe plunger stopper. The fluoropolymer is sufficiently lubricious that the barrel does not need to be lubricated. Another approach to eliminate for example siliconisation is the use of chemical vapour deposition or plasma technology to generate nonsilicone lubricant films on the barrel or piston, or on both.

Together with these new technologies and multiple accessories around the syringe, a real universe of drug delivery components are available, which can be combined to form customised and therapeutic class-focused innovative drug delivery systems.

As an interesting aside, alternative drug delivery routes such as nasal, intradermal or even needle free are being introduced or close to market introduction, yielding individually patient convenient medication systems with a syringe-based primary container for the drug formulation.

CONVERGENCE OF INJECTORS WITH PREFILLED SYRINGES

Returning to prefilled systems in needle-based applications, perhaps one of the most overt developments, most noticeable to the patients and medical professionals who use prefilled syringes, has been the combination of prefilled syringe with safety accessories and injection devices. This has transformed the prefilled syringe from a humble and relatively simple injection device into a true advanced drug delivery system.

Historically we witnessed the emergence of pen devices for the delivery of insulin and human growth hormones. Those therapies typically required injection daily or even several injections daily, and at variable doses. Consequently the devices were able to provide multiple doses from a convenient primary container like a cartridge. A strong focus was on delivering the correct described dose and innovations included digital devices, dose-correction features, larger cartridges, higher doses and smaller dosage increments, to name but a few.

Frequent injection devices were initially reusable, and the users were able to perform up to several hundred annual injections after receiving proper training. The first pen was launched for insulin by Novo Nordisk in 1985. It took longer before the prefilled syringe achieved its current status of the primary container of choice for single- use, fixed-dose auto-injectors.

The prefilled syringe is a different primary container for devices. It is typically a fixed dose and can be up to 1 ml for subcutaneous delivery. This means that the plunger stopper needs to travel all the way through to the shoulder/end of the syringe. Many new therapies for indications such as rheumatoid arthritis, psoriasis, multiple sclerosis, anaemia and Crohn’s disease are fixed doses, given less frequently than every day.

The very first auto-injectors were used with disposable (not prefilled) syringes. Early models were manufactured by Owen Mumford. This concept was then adapted for prefilled syringes.

As they were reusable, there were many steps and they did not prevent accidental needle stick injury after they had been used.
With the new indications a different patient type emerged – some with dexterity issues – most of them demanded as the number one feature ease-of-use, and consequently as few user steps as possible. Other requested features were automatic needle insertion and dose delivery while the needle should not be visible before, during and after the injection, and the needle be locked away after the injection was finalised.

The injection experience could be described best as having just three steps:

1. Remove the cap
2. Place device on the injection site (and release interlock)
3. Press the triggering mechanism

More human factor studies have been conducted and the outcome is visible as it created a wide array of device options: No firing button (i.e. Ypsomed’s Silberhorn); new and different shapes (i.e. Bang & Olufsen Medicom’s Leva®), tamper evidence (i.e. BD’s Physioject™) or numerical cues (i.e. Owen Mumford’s SnapDragon).

The marriage of disposable autoinjector and prefilled syringe also has its challenges:

1. Combination products are now evaluated like a drug by regulatory authorities
2. Project often includes three partners (pharmaceutical company; device maker; prefilled syringe supplier)
3. A larger investment is required as assembly of syringe and device is necessary; furthermore higher capacity tools and moulding machines may be required for high volumes
4. Management of robust large-scale manufacturing, infrastructure, production flow and device/syringe inventories
5. Tighter specifications for prefilled syringe dimensions as delivery of whole dose needs to be guaranteed

Examples for the above exhibiting reduced user requirements are Amgen’s SureClick™ device for Enbrel® and Aranesp® as well as Abbott’s Humira® Pen.

In the years to come the market will see more drugs being launched with the aforementioned disposable auto-injector platforms. New needs for innovation may be driven by high viscosity drugs and volumes higher than 1 ml that need to be delivered via the subcutaneous route. Examples for the former are The Medical House’s ASI and Antares Pharma’s Vibex™.

By Mathias Romacker & Thomas Schoenknecht, both of Amgen Inc

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Warwick Effect Polymers


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