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Pharmaceutical Manufacturing and Packing Sourcer

DIY Dosing

After a massive investment in the NHS in recent years, which has arguably resulted in little extra productivity, the impetus is now on value for money or delivering more ‘bang for the buck’. On the whole, it will be the consumers and healthcare funders who decide where healthcare resources are allocated in their given geographical areas, although legal and political factors may continue to affect the decisions made by the National Institute for Health and Clinical Excellence (NICE) as to the costeffectiveness of individual treatments and drugs. Some healthcare funders have chosen not to sponsor certain drugs or elective operations in their regions, and this is reflected by the persistence of a ‘postcode lottery’ in the UK regarding other aspects of healthcare provision.

Changes in Healthcare Delivery

The current economic climate, as well as the change of government, is producing drastic changes in the way that healthcare must be delivered. As the primary care physicians take hold of budgets once again, more local decision-makers will effectively decide which treatments are available. In addition, there is likely to be far more scrutiny of outcome measures and cost-effectiveness. From April 2011, hospitals in the UK will have to show their patient reported outcome measures (PROMs) – outcome scores that confirm efficacy of treatments and allow calculations of hospital performance. This added responsibility for GPs may well bring an increased awareness of value for money than perhaps was achieved by the past macroeconomic management structures in the NHS. Arguably, GPs are on the ‘shopfloor’ of healthcare and perhaps in a better place to evaluate the overall value for money received by the end-users with an interest beyond the cost of a drug given to a patient, including the costs of clinics, transport, clinicians and primary care.

Total Healthcare Cost

Total healthcare cost is the new buzzword for the fund-holders, who more than ever before must grasp the total overall healthcare costs for treating a patient. In other words, even if a drug is costly, if its prescription results in the patient no longer needing significant primary healthcare support, then overall total healthcare costs may well be lower. For injectable medicines this raises a simple question – will GP fund-holders bear the additional costs for simple injections if patients can self-medicate, and will they tolerate the use of injections that don’t comply with needle-safe statutes?

A district nurse visit costs approximately £80 to £100, while private deliveries of home injections cost up to £1,000 a visit; therefore, the potential healthcare savings produced by technologies that allow patients to self-medicate are substantial. A staggering 85 per cent reduction in healthcare costs (allied to enhanced patient compliance) has been demonstrated for the injectable biological drugs, self-injected at home as opposed to in healthcare settings. Five per cent of the western population have an autoimmune disease, which is likely to be the biggest sector – along with oncology – requiring new injectable biologic medications to come to market.

Patient Factors

Patient education has advanced rapidly in the last few years and the doctor-patient relationship has evolved dramatically. Patients are happier to take responsibility for their own healthcare and now question time-honoured practices. Patients are no longer prepared, nor can they afford to spend time in clinics awaiting simple treatments they know they could easily do themselves and, provided they are offered safe alternatives, are only too happy to self-medicate. For patients, their employers and social security funders, the financial implications of this release from a healthcare-centric existence to normality are self-evident. Pre-filled syringes and auto-injectors are at the forefront of this revolution. From the viewpoint of injectable drugs, two points are very clear:

  • Significant direct cost savings are achieved if patients can self-treat at home with their medications
  • Needle-safe devices are effectively now a statutory requirement to diminish the one million healthcare needle-stick injuries per year in the EU
The Move towards Self-Administration by Auto-Injectors
Considering the NHS requirement for reduced total healthcare costs, in the context of the injectable market, the imperative is on pharmaceuticals that can be self-medicated using suitable auto-injector devices via the subcutaneous, intradermal or intramuscular routes. Studies have shown that auto-injectors provide an 85 to 95 per cent reduction in injectable drug costs compared to the administration of injections by healthcare staff or clinicians based in a primary healthcare setting. Patients, employers and healthcare providers are realising the importance of selftreatment both in reducing primary healthcare costs and improving a patient’s wellbeing – not least because patients no longer have to visit a hospital to receive their medication. Auto-injectors also optimise compliance as they reduce administration errors, thus lowering the risk of disease complications. A comment by a patient sums up the advantages of this method: “Not only did the auto-injector probably cost less than the car parking to attend hospital, but I no longer have to take half a day off work once a fortnight”.

Growth in the Use of Pre-Filled Syringes
The past five years have witnessed major growth in the pre-filled syringe (PFS) market as the importance of safety, security, accurate dosage, anti-tampering and counterfeit protection provided by such devices has been realised by patients, physicians, regulators, healthcare funders and pharmaceutical companies. Clinical research papers provide evidence to support this common-sense view and show that drug administration errors are greatly reduced via the use of PFS. For example, in one study that relied on manual syringe filling rather than pre-filled syringes, it was shown that many incorrect doses of magnesium were given in a one-week period in an intensive care unit (ICU) treating cardiac events, with large dosage errors being observed.The message is that injectable products ideally need to be provided in clearly labelled pre-filled syringes that minimise administration error, and ideally in combination with needle safe devices.

The Need for Auto-Injectors that Incorporate Pre-Filled Syringes
The key point about the design of autoinjectors for pre-filled syringes is that the regulatory route to market is fast and cost-effective. If the primary drug pack, which includes the needle, syringe and stopper, remains unchanged then there is no need to perform further timeconsuming and expensive drug trials.The regulatory environment, cost and time factors are ensuring that PFS remains the format of choice and that auto-injectors are being developed to accept this format without changing the primary pack in any way. In fact,we believe that the use of auto-injectors will become mandatory as the regulatory environment demands injectors that prevent needlestick injury.Healthcare providers are also demanding devices that reduce primary healthcare costs by allowing patients to self-medicate.

Requirement for Needle-Safe Devices
Major international imperatives are underway to further regulate healthcare environments in an attempt to reduce the incidence of needle-stick injuries. In the US, 500,000 sharps injuries are reported each year (with up to another 50 per cent going unreported), with similar numbers in Europe. In general, healthcare workers report 0.5 to 3.4 sharps injuries per year. Similarly, patients who self-medicate have voiced concerns over the safety of family members in a home environment where there are unprotected needles.

The NHS and private healthcare suppliers in the UK are waking up to the financial implications of needle-stick injuries. Recent payouts to individuals as a consequence of receiving a needlestick injury have been in excess of £1 million when healthcare providers have been found to be at fault.The authority responsible for liability within the NHS has made it clear that defending such incidents would be impossible unless the healthcare providers had taken all steps reasonably possible within their financial constraints to ensure adequate needle safety. Although individual hospitals trusts have Crown indemnity, insurance premiums reflect local trust risk management practices – so every needle-stick injury directly affects the resources remaining for healthcare provision.

It is clear that the days of non needlesafe vials and ‘naked’ needles are over. Auto-injectors require needle safety with features that prevent accidental needle-stick injury and pharmaceutical companies are rushing to upgrade first generation auto-injectors with inadequate needle safety.

Major Market Growth in Biologics Developed in Pre-filled Syringes
The global pharmaceutical market is now worth approximately $600 billion and most analysts are predicting that 15 to 40 per cent of pharmaceutical revenues will be from biologics by 2015. While some companies such as Roche spotted the upcoming growth in the biologics market as early as 1990 by merging with Genentech and are currently market leaders in the biotechnology industry with revenues from biologics at $36 billion in 2009 (followed by Amgen with revenues of $14.7 billion), some of the other large pharmaceutical companies have not yet followed this pathway.

A number of other major pharma companies were forecast in 2010 to generate no sales from biologics, instead relying on revenues from traditional small molecule product sales.However, even companies such as AstraZeneca and Merck & Co have recently made bids to acquire biological drug development and some are even considering the previously unthinkable option of competing with their own generic versions. Pfizer said it would follow Merck and other companies into the area of biosimilars and biologics with a further three follow-on products for rheumatoid arthritis in Phase III development.Merck also said it expects to seek regulatory approval of five new drugs with 45 per cent of its clinical pipeline coming from its takeover of Schering-Plough. Even Novartis, which was forecast to record the second strongest growth rate in big Pharma in 2010, has decided to enter the generics market as well as positioned itself strongly to enter the emerging biosimilars market.Whichever pathway the large pharmaceutical companies have chosen, it is clear that biologics will become a major part of the pharmaceutical revenue of the biggest companies and that this will be reflected by the increased development and use of pre-filled syringes.

New Injectables and Pre-Filled Syringes

There are currently around 550 biological therapeutics (antibody-based drugs) in late stage development and about two thirds of the injectables are in PFS format. There are 30 branded antibodies currently available on the European market with worldwide sales of $129 billion. Five products dominate the biologics market – with Avastin, Remicade, Rituxan and Humira accounting for 75 per cent of sales – and many of the current drugs are administered using auto-injectors. The patents of many of the currently available biological drugs have already expired or will expire in the next few years, and although there are no generic monoclonal antibodies approved in the US or Europe, they are predicted to reach the market between 2014 and 2016. New entries to this market will have to compete not only in terms of cost and bioequivalence, but also in terms of the ease and cost of administration.

The message is clear: if you have an injectable, it has to be cheaper, as effective as the previous product and it must have a PFS, ideally with an autoinjector for self-administration, as well as meeting all needle-safety regulations. If you do not have an auto-injector, you should be aware that all of your competitors will.

Growth in High Viscosity Injectables – Protein, Sustained Release and Depot Formulations
The new antibody-based biological therapies often have high viscosity as they must be delivered at high concentration in small volumes. In addition, the market need for reduced dosage frequency is being met by PEGylation and related technologies, sustained release and depot formulations, which also tend to have very high viscosities.

Patients cannot self-administer high viscosity formulations as they are challenging to inject even for healthcare professionals – very high forces are required to inject viscous fluids through fine gauge needles. Fine gauge needles are required to minimise patient pain but the use of conventional syringes is currently a commercial requirement as it greatly reduces the regulatory challenges and the cost and speed to market.This means that there is a growing market need for medical auto-injectors that can deliver high viscosity drugs using conventional needles and syringes.Given the regulator’s preference for zero per cent failure rate, first generation devices cannot currently meet this challenge and even low viscosity formulations often require a significant force that can result in a high percentage of glassware failures.

Manufacturers have developed specialised syringes to cope with the forces required for viscous drugs and have worked to improve the manufacturing tolerances that affect auto-injector performance. Recently we have seen the emergence of plastic syringes, such as CZ materials, which claim to offer enhanced protection, although they may have different compatibilities with biological medicines compared to glass.

Perhaps the key requirement is that new auto-injectors for delivery of high viscosity biologics must be able to use the existing packaging formats. Autoinjectors for viscous drugs must be easy to use, leave the primary pack unchanged and meet emerging global needle-stick regulations.

Lyophilised Drugs

Exponential growth is also expected in the lyophilised drug sector.There are few, if any, devices available to deliver these products in an acceptable manner. Such drugs require a multi-chamber, multistep process to reconstitute the drug and then deliver it. New auto-injectors for lyophilised drugs are also emerging but they face the same challenges of ease of use, patient conformity and safety.

Conclusion

The major market for injectables is moving towards the development of biologic and sustained-release medicines in pre-filled syringes combined with auto-injectors, or towards lyophilised presentations.Newer products need new devices, as most existing devices fail to deliver drugs of any significant viscosity and only a few meet emerging needlestick regulations.New syringe and cartridge designs are similarly required, and devices are needed to deliver the exponential growth expected with lyophilised presentations.The major driver with the new biologic and sustained release drugs is a reduction in overall healthcare costs. Selfmedication reduces primary healthcare costs by as much as 85 per cent and providing needle-safe devices significantly reduces the incidence and cost to the healthcare providers of third party needle-stick injury.

In addition, PFS and auto-injectors have been shown to markedly increase compliance even with well-established medicines, again contributing to improved healthcare outcomes and a reduced overall cost of treatment.The regulators are demanding needle-safe devices and the healthcare providers and patients are demanding autoinjector solutions for the cost and lifestyle benefits that they produce.The major emerging challenge is to develop auto-injectors that can use the existing delicate glass PFS, thereby avoiding expensive re-regulation, to deliver the many emerging viscous medications. They must achieve this without breaking the syringes and with zero failure rates. While only a limited number of devices are out there, there are hundreds of new drugs coming to market, some of which have very specific physical requirements demanding newer auto-injector capabilities, and with many disease areas fully and exclusively licensed. Eventually, there will be a shortage of auto-injector intellectual property to meet demand, and late-comers to the market may find themselves unable to deliver their product.



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Bob Sharp is the Medical Director of Future Injection Technologies (FIT) Ltd. A Consultant Orthopaedic Surgeon at the Nuffield Hospital, Oxford, he leads their departmental research team and has a special interest in rheumatological diseases. He has been widely published and his current roles include advising NICE on modern technologies in his field, as well as being Medical Director of the JAGB. Bob undertook his medical training at Cambridge followed by Oxford. He then completed his orthopaedic training on the Oxford Rotation before completing a Fellowship in Australia. He was awarded the Gold Medal by The Royal College of Surgeons of England for The Most Outstanding Achievement in the FRCS Trauma and Orthopaedics exam in 2000, and was awarded The President’s Travelling Scholarship in 2001. Email: bob@futureinjection.com

Paul Whyte is Chief Executive Officer of Future Injection Technologies (FIT) Ltd. He has experience in commercial leadership roles spanning the pharmaceutical, academic and emerging technology environments, from partnering late-stage pharmaceutical products to exploiting innovative emerging products and technologies. Paul was responsible for leading the commercial development and partnering of therapeutic medicines at Evolutec plc as Director of Business Development, and prior to this for partnering the cancer and inflammatory therapies and therapeutic discovery platform at Avidex Ltd (Medigene). He also spent several years at Cancer Research Technology (CRT) in a commercial role, and was instrumental in forming a joint venture company – Cancer Therapeutics Limited – with Antisoma plc to develop a late-stage cancer therapy. He has an honours degree from Warwick University, a PhD in Immunology and an MBA. Email: paul@futureinjection.com

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