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Pharmaceutical Manufacturing and Packing Sourcer

A Design for the Times

The dynamics of the pharmaceutical market are rapidly evolving, due to catalysts such as unmet medical needs, the introduction of new drugs and a keen focus on healthcare costs, including the ever-increasing generics market.Other drivers changing this marketplace include evolving regulatory standards, the expanding emerging market sector, the need to prolong market shares of drugs coming off patent in the near future through the use of differentiation and life cycle management strategies, and more emphasis on patient compliance and convenience. In this article existing device technologies will be reviewed and we will look at how all the above factors are currently driving emerging device technologies in these drug delivery areas.

Nasal Drug Delivery

Pharmaceutical metered nasal spray pumps have been around for more than 40 years and are the drug delivery device of choice for ailments such as nasal congestion and allergic rhinitis, which between them have more than 350 million sufferers worldwide. Recent pressure from regulatory authorities, including the distribution of guidance documents, have focused on the chemistry, manufacturing and control (CMC) aspects of these products, looking to measure and control some of their critical quality attributes such as dosing and spray performance (1). In response to this, device manufacturers are developing a new generation of nasal spray pumps with improved performance and robustness to meet these requirements.

An example of this is CPS drug delivery technology.This type of pump incorporates technical advances such as pre-compression – which leads to more consistent dosing due to decreased dependence on patient actuation forces – as well as spring loaded tip-seals that give a much longer and stable spray phase. In a conventional system, only 30 to 40 per cent of a dose is delivered during the fully developed phase, compared with over 80 per cent when using CPS (see Figures 1 and 2).Technical advances like this have also led to optimised droplet size distribution.

A unique property of CPS is that there are no metal contact parts in the fluid or drug product path. CPS can also provide life cycle management opportunities; it can be used with preservative-free formulations – as this pump meets microbial challenge testing – and can consistently deliver a non-preserved drug product throughout its lifespan. Opportunities in emerging markets where low cost, ease and simplicity of use are essential have seen nasal spray systems introduced for treatments of diseases such as influenza using disposable nasal unit dose systems – for example,Nasovac from the Serum Institute of India (2). Nasal sprays are also gaining market share in the breakthrough pain management arena with recent launches of Fentanyl-based products such as Instanyl from Nycomed and PecFent from Archimedes Pharma in Europe.

Devices for pulmonary aerosol delivery, such as pressurised metered dose inhalers (pMDIs), DPIs and nebulisers first appeared in the marketplace more than 50 years ago, and more than 600 million devices are manufactured every year. DPIs are gaining market share, in particular for asthma and chronic obstructive pulmonary disease (COPD) medications, as well as more recently with anti-viral drugs.Numerous innovations have emerged in the DPI area including patient convenient multi-dose devices, which contain 30 or 60 doses, and incorporate a dose counter and/or other dose delivery signals or feedback, such as visual, auditory and safety features to avoid double dosing. One such device is the Prohaler DPI (see Figure 3), which was developed with extensive user focused design studies, ensuring that the product is easy to teach, intuitive, easy to use and portable; indeed, it incorporates many of the features mentioned above. In addition, the inhaler has been tested extensively in the clinic with asthmatic and COPD patients in order to optimise key performance characteristics such as breath triggering levels, air flow and powder delivery performance.

Ophthalmic Delivery

According to the World Health Organization, about 314 million people worldwide suffer from impaired vision, and 45 million are fully blind (3). Increasing numbers of people are at risk of age-related visual impairment as the global population grows and demographics shift towards a higher proportion of older people, even in developing countries. For chronic treatment, multi-dose containers would be the preferred, most cost-effective option. Few options are available for ophthalmic use, and most of the current packaging concepts require preservatives in the formulation stage to guarantee microbial stability and sterility.The major, preservative-free alternative established on the market is single-dose blow-fill-seal containers.

An adaptation of an approach that is well established for preservative-free nasal spray systems – a mechanical seal technology combined with sterile filtration of the venting air – provides a highly effective delivery system. A springloaded tip-seal keeps the system closed until a defined pressure is reached during actuation.The formulation is then forced through the orifice.When the pressure drops as a result, the tip seal immediately closes the orifice by an outward motion, which prevents any backflow of contaminated liquid or particles. For the venting air, a sterile filter (0.2μm nominal pore size) is used to stop microorganisms from entering.As some ophthalmic formulations have compatibility issues with metal, the design of the ophthalmic system features a metal-free fluid path.

One device that has emerged from the development process is the ophthalmic squeeze dispenser (OSD).The OSD is actuated by squeezing a modified 10ml low-density polyethylene (LDPE) bottle and the device can easily be adapted for a reasonable range of viscosities which allow the delivery of a consistent drop size (see Figure 4).

This new generation of multi-dose ophthalmic devices, with all their advantages, can provide the cutting edge for the life cycle management of established products,with low investments in filling technology.

Encouraging Compliance

With the current difficulties in the world economy and the subsequent pressure on healthcare costs worldwide, more companies are looking into patient compliance as a means of reducing the burden on the healthcare system. Lack of compliance – that is, not taking the right dose of the right medication at the right time for the prescribed duration of a treatment – has significant cost implications if medication is wasted, or the patient requires additional treatment due to poor compliance, and at worst can actually be harmful to patients (4). In order to address this issue, products are being developed by the industry to aid compliance, two examples of which are side actuation nasal spray technology and a family of electronic devices specifically aimed at improving patient compliance (see Figure 5). Aspects such as ergonomics, handling comfort and ease of actuation were the main drivers in development, and feedback from the end users confirmed improvements in all these areas.

Another potentially powerful addition to the patient compliance area is the use of electronic devices such as e-counters, elockout systems and data monitoring.To address compliance needs, a platform of edevice technologies is also in development which can be incorporated as part of the drug delivery system.Such devices can help patients to count their doses and, consequently, to see how many doses remain before they need to refill their prescriptions. In addition, electronics can allow self-dosing of treatments such as breakthrough pain medication, without direct healthcare professional supervision,and can protect the patient with lockout systems that would prevent accidental overdosing or diversion with potentially potent controlled substances.All these developments offer excellent opportunities to enhance patient compliance and can eventually be part of integrated electronic healthcare provider systems, which could become standard in the future.

Conclusion

There are many new and innovative developments emerging in the nasal, pulmonary and ophthalmic drug device delivery areas, all aiming to meet the evolving needs of these markets, such as stricter regulatory standards and life cycle management.The patients themselves should also benefit from some these innovations as they also contribute to patient compliance and will bring significant benefits to users, and help manage healthcare costs in an ever-evolving world.

References

1. Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products Chemistry, Manufacturing and Controls Documentation, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2002
2. www.seruminstitute.com
3. WHO Fact Sheet No 282, Visual impairment and blindness, May 2009
4. WHO Adherence to long term therapies, Evidence for action, 2003 report




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Gerallt Williams obtained his PhD from the University of Wales in 1985, and subsequently held various industrial positions at a range of companies, including Monsanto Inc, Fisons Ltd, Valois and Inhale/Nektar Therapeutics. He is now Director of Scientific Affairs for the Aptar Pharma Prescription division, Le Vaudreuil, France and is involved in the development of new devices for nasal and inhaled drug products.
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