Plastic Pre-fillable Syringes and Vials: Progress Towards a Wider Acceptance

A number of trends can be identified in the delivery of parenteral drugs in the last decade. Amongst these is the increase in popularity and sales of pre-filled syringes, a growing availability of ready-to-fill plastic pre-fillable syringes, and the outsourcing of the final preparation of primary packaging components from the pharmaceutical companies to the component vendors. Annual global sales of pre-filled syringes are currently estimated to be over 2.2 billion globally, with over 50% of the units being supplied in nests (tubs) as ready-to-fill components [1]. Here washing, siliconization and sterilization of the components is already completed (nested) as against being supplied in bulk where these steps are the responsibility of the pharmaceutical company. In 2005, a previous article on plastic vials and plastic pre-fillable syringes reviewed the status of both their availability and interest in their use as primary packaging for parenteral products [2]. This article will examine what progress has been made in the availability of plastic pre-fillable syringes and vials, whether there has been a change in attitude of pharmaceutical companies to their use, and to review the regulation of plastics for containers.

Materials

Polypropylene pre-fillable syringes and vials have been available for a number of years either manufactured in-house by pharmaceutical companies or obtained from a custom molder. Polypropylene pre-filled syringes are widely available in sizes between 2 mL and 50 mL and contain commonly used generic drugs such as saline, heparin, atropine and epinephrine in small volumes and electrolytes such as sodium bicarbonate in larger volumes for use in hospitals and emergency vehicles, etc. More specialized designs have been developed containing x-ray contrast media that are extruded by x-ray power injectors for procedures such as computed tomography imaging and cardiovascular angiography. These syringes range in size from 50 mL to 125 mL. Polypropylene vials containing parenteral drugs do exist but are relatively uncommon. Use of plastic instead of glass for contrast media and oncology drugs has been promoted as a safety feature by reducing the risks of sharps-related injuries from broken glass bottles and metal-pull rings [3]. In addition, disposal of plastic containers as medical waste offers savings in weight, especially for containers over 100 mL.

While polypropylene has remained the material of choice for inexpensive drugs, diluents and electrolytes, cyclic olefins have become the plastic of choice for new drugs. Cyclic olefins are sub-divided into cyclic olefin copolymers (COCs) and cyclic olefin polymers (COPs). COCs are produced by polymerization of cyclic monomers such as norbornene with ethane while COPs are produced by ring-opening metathesis of cyclic monomers followed by hydrogenation [2,4]. The manufacturing process can be carefully controlled to provide a range of glass transition temperatures (Tg) ranging from 70ºC to 180ºC, depending on amount of cyclic monomer present [4]. The cyclic olefins have very attractive properties for the manufacture of pre-fillable syringes and vials such as excellent optical transmission, low birefringence, high purity, low moisture uptake and an excellent moisture barrier [2,4-6]. Cyclic olefins do have some drawbacks in that they are moderately permeable to gases [7] and should not be used with high concentrations of fats or oils or with non-polar or halogenated solvents [5].

Table 1. Packaging Components Available in Cyclic Olefins

Plastic Pre-fillable Syringes and Vials

The commercial availability and properties of cyclic olefins has led to their selection as the material of choice for the construction of clear pre-fillable syringe barrels and vials by the leading manufacturers of containers for pharmaceutical use. These manufacturers have limited their material selection to three cyclic olefins, two COP formulations and one COC formulation [2]. The available sizes for pre-fillable syringes range from 0.25 ml to 150 mL, the particular size range varying with the individual company (Table 1). These designs are not available with a needle permanently affixed to the barrel (staked needle) whereas staked needles are readily available with glass pre-fillable syringes. It has not all been positive growth in this decade since one pre-fillable syringe system using a COC barrel was discontinued in 2008, with the company taking an impairment charge of $31 million [9]. Two plastic vial types are available, a standard design and a second type described as a closed vial. The closed vial represents a new approach to vial handling and filing operations. The COC vial body and stopper made of thermoplastic elastomer are injection molded and assembled immediately under clean conditions and gamma sterilized. Filling of the closed vial is achieved by piercing the stopper and then immediately resealing the puncture with a laser to re-establish closure integrity [10-11]. The design won the ISPE and INTERPHEX “Facility of the Year Award” in the category of Equipment Innovation in 2009 [12]. The system was developed for aseptic filling of parenteral products since the container-closure system is not suitable for terminal sterilization due to the thermoplastic nature of the closure. This concept has now been extended to using these closed vials for lyophilization using an additional device called a penetrator that keeps open the pierced channel in the closure created by the filling needle during the lyophilization process. A study using various excipients has shown that lyophilization is successfully achieved with COC vials using this technology [13]. In another study, a polymer-conjugated platinum anticancer agent was successfully lyophilized in COP vials and remained stable for the six-month stability study period [14]. Sterile screw capped containers are also available for use for drug product storage and transportation. These containers are not nested but are supplied individually wrapped and vacuum packaged (Table 1).

Areas of New Product Development

New designs and approaches have been either recently launched or are under development to augment the currently available product lines. For example, sterile, ready-to-use COP vials and COP cartridges are now available as well as COP dual-chamber designs (Table 1). One product being developed is a plastic pre-fillable COP syringe with a needle permanently affixed to the barrel. This design, referred to as an insert needle (IN), does not require adhesive to hold the needle in place [15]. Another area of research is to add a barrier coating to plastic syringe barrels to decrease oxygen permeation.

Drivers to Select Plastic Over Glass

Over the last three years I have observed an increased willingness to consider the use of plastic pre-fillable syringes manufactured from cyclic olefins for the development of biotechnology drugs. There are a number of factors that have helped drive this increase in interest. These include the availability of a range of sizes supplied as ready-to-use components from the leading vendors of pharmaceutical packaging components as shown in Table 1. Also, there is a concern in regard to the potential interaction of certain protein molecules with glass surfaces [16] and with residual tungsten having the potential to cause aggregates with specific proteins [17]. The source of the residual tungsten is from the tungsten wire used to maintain the fluid channel during the formation of the nozzle of glass pre-fillable syringes. Molded plastic barrels do not utilize tungsten wire in their manufacturing process. Glass pre-fillable syringes and most plastic pre-fillable syringes require lubrication as supplied by silicone. The presence of silicone has been reported to induce protein aggregation and so remains a concern with sensitive biotechnology molecules [18]. The presence of silicone can be avoided by selecting a silicone-free plastic pre-fillable syringe system that combines a COP barrel with a coated plunger [19].

This interest in plastic will be further helped by the availability of a range of cyclic olefin components that allows experience with product contact starting with storage of the bulk active ingredient in a plastic container, proceeding to phase I clinical supplies in plastic vials, then to plastic pre-fillable syringes for phase III clinical studies and launch followed by a plastic cartridge for an auto-injector to enhance the product life cycle. All these components would be manufactured from the same cyclic olefin. This development philosophy would be equivalent to product development in glass components that proceed from glass vials to glass pre-fillable syringes to glass cartridges for auto-injectors, all manufactured from Type I glass. Such a range of plastic components is becoming available (Table 1). A number of products are now being marketed in COP pre-fillable syringes and vials, especially in Japan, with a smaller number in Europe and the USA. These include x-ray contrast media, MRI contrast media, and hyaluronic acid in pre-filled syringes and anti-fungal and oncology products in vials [20].

Regulation of Plastic Containers

Regulatory authorities require detailed information on the manufacture and composition of packaging components. This is more complex for plastic components since they consist of a number of organic molecules comprising not only the polymer itself but also additives such as stabilizers, anti-oxidants, processing agents and colorants. Guidelines on what information is required may be found in the European “Guideline on Plastic Primary Packaging Materials” [21] and in the FDA’s “Container Closure Systems for Packaging Human Drugs and Biologics” [22]. Both the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) contain chapters relevant to plastic packaging materials, but there are a number of differences in the requirements. In the case of the USP, plastic containers must meet the requirements for biological testing as detailed in general chapters <87> and <88> [23, 24] and physiochemical testing as provided in general chapters <661> Containers – Plastics and <671> Containers – Performance Testing [25, 26]. Chapters <661> and <671> were revised in 2005 when glass containers were moved from <661> to its own chapter <660> Containers – Glass [27]. Some editorial changes were made to <661> Containers – Plastics but the tests and specifications for polyethylene, polypropylene and polyethylene terephthalate (PET) containers were unchanged. Testing is limited to two identity tests (IR and DSC), tests for heavy metals and nonvolatile residue on solution extracts plus buffering capacity added in the case of oral liquids. Tests for total terephthaloyl moieties and ethylene glycol are present for PET. All other plastic containers are required to undergo testing for nonvolatile residue, residue on ignition, heavy metals and buffering capacity on solution extracts (physicochemical tests). So, in the case of cyclic olefins for parenteral use, they must meet both the four physicochemical tests in <661> under “other” plastics and the biological tests in <87> and <88>.

The approach to the control of plastic containers in the European Pharmacopoeia (EP) is quite different with tests and specifications being set for individual polymers for particular medical applications as well as for plastic containers. Section 3.1 of the EP on “Materials Used for Manufacture of Containers” [28] has very detailed individual chapters on polyvinyl chloride, polyethylene, polypropylene, polyethylene vinyl acetate, PET and polyolefins. The chapter on polyolefins that is relevant to cyclic olefins, has three identification tests and nine tests on solution extracts including tests for extractable aluminum, titanium, zinc and heavy metals [29]. In the section on plastic containers [30], the EP has tests and specification for plastic containers for solutions for aqueous infusion [31] but not for parenteral products in general. The EP is silent on the biological testing of individual polymers or plastic containers.

There is another difference between Europe and the United States on the mechanisms to supply information on plastic formulations. Canada and the USA have a Drug Master File (DMF) system where companies can provide confidential information on the constituents and manufacturing process for their products. Information on packaging materials can be supplied in a Type II DMF in Canada and in a Type III DMF in the USA [32]. There is a DMF system in Europe but it is limited to providing information on drug substances. Therefore, European drug application must contain the required information on the packaging materials.

In summary, there has been progress in developing new plastic containers in convenient, ready-to-use configurations coupled with a greater willingness in pharmaceutical companies to consider plastic containers over glass, especially for sensitive molecules. Confidence in selecting cyclic olefin containers will steadily rise as more pharmaceuticals are approved using this type of plastic.

References

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Dr. Michael N. Eakins is the Founder and Principal Consultant of Eakins & Associates, based in New Jersey, with over 25 years experience in pharmaceutical research and development having worked for the Medical Research Council (UK), and E. R. Squibb & Sons, Bristol-Myers Squibb and Bracco S.p.A. in the USA. Michael provides advice on non-clinical drug development and parenteral packaging, especially pre-filled syringes and anti-counterfeiting technologies and lectures on these topics worldwide. Michael holds a B.Sc. Hons in Physiology and Zoology and a Ph.D. in Physiology from London University, UK and has contributed to 55 publications and holds eight U.S. patents.
To correspond with author, please e-mail him directly at: [email protected]

This article was printed in the January/February 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 1. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.