Some markets are seeing greater demand for preservative-free products. Dr Degenhard Marx and Matthias Birkhoff, Aptar Pharma Radolfzell, discuss the opportunities and technology.
Multi-dose dispensers are widely used for liquid medications because of convenience and cost effectiveness. As of today, most of the available dispensing devices are designed to contain preserved formulations, but for some years now so-called ‘preservative-free multi-dose devices’ (PFMD) have been on the market and have gained substantial share. It is estimated that out of 220 million metering nasal spray pumps for nasal decongestants sold worldwide in 2011, one third were PFMD.
The driver behind this is the growing number of patients who experienced discomfort with preserved formulations – something that attracted the scrutiny of the responsible authorities. Also, scientific data and clinical findings suggest that preservatives are not completely harmless. So for many brands the classic preserved product can be found next to a ‘preservative-free’ label.
It is hard to provide precise figures on PFMD, especially as there are some geographical market preferences. The European authorities have started to tip the balance in favour of unpreserved medications; however, the US and Asian authorities still like preservatives. Thus the largest markets for preservative-free multi-dose devices are Europe, in particular Germany and France, and Latin America.
Use of preservatives in multi-dose products
Multi-dose dispensers are widely used for the administration of liquid nasal, ophthalmic or dermal drugs because they are cost effective. To prevent degradation of the product and to avoid the spread of potentially harmful microbes the content has to be kept sterile. This requirement is in most cases met by a closely controlled manufacturing and filling procedure and by placing a suitable preservative in the formulations. Benzalkonium chloride (BAC) is by far the most widely used preservative, but thiomersal, chlorhexidine, chlorobutanol and phenylethanol, and parabens can also be found in topical medications.1
Two general issues are linked to the use of these preservatives, one of which is the choice of packaging materials. This is certainly of primary importance for the manufacturer. Traditional glass containers do not interact with preservatives, but more and more plastic containers and dispensing devices are being used that may pose problems due to permeation of preservatives through the container or interaction with the plastic materials used in them. Rubber also reacts with preservatives but it is still used for closures, which in such events have to be pre-treated with the preservatives to minimise subsequent uptake during storage.
Microphotographs of the membrane (pore size of 0.22µm) used for the production of the filters
The issue of significance for the patient and consumer, however, is the high incidence of local side-effects attributed to preservatives. The discussion is controversial, and published preclinical and clinical studies are not always consistent. It seems to be clear that short-term use of preparations containing preservatives at low concentrations is well tolerated, but with long-term use preservatives can cause serious inflammatory effects. The responses may include chemical irritation, hyperreactivity and true allergies.2
The German Authorities (BfArM) addressed the use of BAC for nasal sprays in 2003,3 which pushed the preservative-free systems for this administration route. In 2009, European authorities encouraged the use of unpreserved medications for ophthalmic use.4 The currently circulated EMA draft guideline on Pharmaceutical Development of Medicines for Paediatric Use5 requires that the use of any preservative should be justified in nasal preparations. For ophthalmic preparations this draft guideline is even stricter: ‘In order to avoid the use of preservatives with potential local toxicity to the cornea and/or mucous membranes, single-dose preparations or multi-dose preparations in a dedicated multi-dose container that does not require its contents to be preserved, i.e. preservative-free containers, should be considered for children, especially neonates. This is especially important if long term use may be necessary.’
PFMD devices have the potential to solve some of the problems faced by pharmaceutical manufacturers (e.g. incompatibilities), meet the request of the European authorities and offer marked benefits for patients in need of chronic treatment.
When using a preserved or unpreserved multi-dose product, there are three ways for micro-organisms to enter the system:
- via the orifice and
- via the venting air which is replacing the dispensed liquid or
- insufficient container/dispenser fit.
In preserved formulations (dispensed by conventional systems), the added preservative controls microbial growth and no additional measures need to be taken to prevent microbial occupation via the orifice or venting air. If the formulation does not contain preservatives, the device must be able to keep micro-organisms out of the system.
Technologies for preservative-free multi-dose dispensers
Today a range of technical solutions is available to keep the content of multi-dose dispensers sterile. The highest risk of contamination obviously comes from the orifice, because it may come into contact with skin and mucosa that are populated by normally harmless micro-organisms as well as with potentially infected body fluids. Some marketed systems use the oligodynamic activity of silver.6 The released silver ions reduce micro-organism numbers between long dosing intervals, even when the tip is immersed in bacterial contaminated fluid.7
The most recent preservative-free systems follow a purely mechanical approach to minimise interactions between parts of the device and the formulation. One technical solution to prevent contamination via the orifice is named ‘tip seal technology’, which may be utilised for spray pumps and ophthalmic droppers. A spring-loaded valve is located directly below the opening of the tip orifice and does not allow any microbes to migrate from any surfaces or contacted liquids into the system; the orifice is hermetically ‘sealed’ under resting conditions.
Sterile filter for the venting air ready for assembly into PFMD systems
The tip seal keeps the system closed until a defined pressure is reached by actuating the system. Then the system will open and the formulation is forced through the orifice with a higher pressure than needed to open the valve. When the pressure drops at the end of the actuation the tip seal will immediately close the orifice with an outward movement, preventing backflow of potentially contaminated medication or other liquid. Depending on the pump system, the fluid path may even be ‘metal-free’, which means the springs needed for the device operation do not come into contact with the formulation.
At any time when a liquid is dispensed out of any container, the pressure inside decreases gradually. To avoid contamination of the formulation via the venting air different technical solutions are used. The simplest way is sterile filtration of the venting air using separate filters or filter gaskets. For oxygen-sensitive formulations, so-called collapsing bags or depressed systems are used.
The formulation is filled in a special, microbial tight bag, which is protected by a surrounding bottle. When dispensing the product, the bag collapses with the content not coming into contact with the ambient air. Some pumps are designed in such a way that the entire system is air-tight and during use a vacuum is generated within the bottle.
These approaches to avoid the use of preservatives for multi-dose devices sound complicated but are well-established and mature technologies. Preservative-free single-dose containers, most often presented as blow-fill-seal (BFS) containers, are an alternative for short term treatments. Disadvantages of these systems are linked to the complicated filling technology, the need to substantially overfill and the relatively high amount of packaging material needed for each dose.
| Table 1: Measures/technical solutions for preservative-free multi-dose devices | |
| Prevent contamination via orifice | |
| Oligodynamic components in the actuator or inside the pump | Open orifice, silver-ions are released into the formulation, which kill germs by interacting with the formulation |
| ‘Tip-seal’ technology | Mechanical barrier system to prevent bacterial contamination |
| Prevent contamination via venting air | |
| Sterile filter incorporated into delivery system | The venting air in pressure balanced systems is forced though sterile filters with pore sizes less than 0.2µm; the filter membranes are normally hydrophobic, which prevents leakage of liquids out of the container via the venting system |
| Collapsing primary container | Suited for oxygen-sensitive formulations because the venting air does not come in contact with it, this technology also enables spraying at different angles |
| Unvented container/pump system | Tight fit of bottle and pump design prevent venting of the bottle, vacuums up to 300mbar are reached |
Manufacturing and filling of PFMD devices
The device as well as the bottle should meet highest standards related to the manufacturing process. The moulding of the device parts and the assembling requires a controlled environment, and in some cases cleanrooms, mainly Class 7, are used to reduce the numbers of particles and to keep the bio and particulate burden of the devices low.
The same applies for bottles. In most cases the devices and bottles are delivered sterile to the filler. Here the medication is filled under aseptic conditions into the bottles and the delivery device, such as a spray pump or ophthalmic dropper, is attached.
It should be pointed out that an irremovable connection between the bottle and the dispenser is crucial. This requires a sophisticated and validated device handling and filling process. The alternative way is filling under controlled but not sterile conditions and subsequent final sterilisation of the finished product. For final sterilisation radiation is commonly used, but not all formulations and devices will withstand this procedure.
Assembly line for the production of a PFMD nasal spray pump system
Is the future of liquid medications preservative free? The answer is not as easy as it seems, because cultural aspects are no less important than regulatory aspects and safety concerns. However, in Europe a trend towards preservative-free multi-dose formulations is seen. Any development of novel drugs or research on life cycle management should take this into serious consideration. Preservative-free products can provide cutting edge technology for the lifecycle management of established products and will be appreciated by the high number of patients experiencing side-effects with preserved formulations.
References
1. Freeman DP, Kahook MY., Expert Rev Ophthalmol. 2009; 4(1): 59-64
2. Hong J and Bielory L., Curr Opin Allergy Clin Immunol 2009; 9(5):447-453
3. Bescheid des Bundesinstitut für Arzneimittel und Medizinproduke für benzalkonium-chlorid-haltige Arzneimittel zur Anwendung in der Nase, A 37489/38186/03 Bonn, Dezember 2003
4. EMEA Public statement on antimicrobial preservatives in ophthalmic preparations for human use. EMEA/622721/2009, London 2009
5. EMA Guideline on pharmaceutical development of medicines for paediatric use. EMA/CHMP/QWP/805880/2012 Rev. 1, London 2013
6. Gross D. The COMOD-System – a preservative free drug therapy against glaucoma. 321-328, in Orgül/Flammer (Editors): Pharmacotherapie in glaucoma, Bern 2000
7. Bagel S, Wiedemann B., Europ J Pharmaceutics and Biopharmaceutics. 2004, (57): 353–358