What, in your opinion, is currently the single largest trend with respect to the application of drug delivery technology, specifically pre-filled syringes and auto injection devices?
AJ: Tighter specifications and glass barrel designs that help avoid glass breakage (i.e. smaller flange).
AS: Drugs, particularly biologics, are becoming more novel, specialized and patient-centric. Delivery devices must reflect this. As such, devices are increasingly being customized to meet the specific molecular and dose administration requirements of the target drugs. Because this trend towards drug-device specialization is occurring at the same time that therapeutic classes are becoming more competitive, the need for product differentiation is also becoming more acute. Devices that carry some level of market exclusivity and can thus deliver powerful brand differentiation and enhance patient care are highly desired. Having a ‘me-too’ prefilled syringe or an auto-injector is no longer enough. The more superior the prefilled syringe in terms of safety, convenience and ease-of-use, the greater your chances of beating the competition in a particular therapeutic drug class.
RH: The trend has been and will continue to be self-administration. The aforementioned drug delivery technologies work very well together to this end. Ensuring that there is an easy and safe means of providing therapies to patients is everyone’s primary objective.
SD: Although injection devices such as the reusable pens for chronic conditions such as diabetes have been around for more than 30 years, only for the past 3-4 years, has there been a significant interest in injection devices to pharma, biotech and generic companies.
The shift in focus from inpatient hospital care to treatment at a home setting to manage chronic conditions are reasons for pharmaceutical companies to look for an injection device that offers convenience and patient acceptance.
Injection devices are rapidly becoming an important strategy in the life cycle management of diseases to treat chronic conditions whether it is migraine or rheumatoid arthritis.
For some therapeutic areas such as multiple sclerosis, the auto injector device is now becoming the standard method of delivery for this therapy.
With the loss of patent protection for some of the biologics, generic companies are also looking to enter the drug device marketplace for biologics resulting in an increasing demand in auto injectors.
Delivery of viscous drugs is gaining increasing prominence as pharma companies seek to reduce injection volumes by developing more concentrated formulations and as more pegylated drugs come to market.
CH: Higher quality expectation towards “zero defects” e.g. with respect to cosmetic/ visual, dimensional and functional defects, especially for syringes in interaction with devices.
AF: The driver of interest in pre-filled syringes and auto injectors is the pipeline of biologic drugs that have to be injected and the need to support self-administration of them. Additionally, there is a life-cycle management drive towards self-injection devices that make the self-administration of injected therapy easier, simpler, and more acceptable - i.e. from pre-filled syringes to auto injectors.
There is also a current regulatory pressure to ensure that usability/human factors issues are thoroughly addressed by self-injection device developers, demanding attention to detail with regard to the usability of devices.
How, in your mind, has the landscape of drug delivery shifted post-recession?
AJ: I don’t see that the recession per se had a big impact on the landscape of drug delivery. It’s the kind of drugs that are coming to the market and their injection requirements that dictate the drug delivery device landscape. Drugs are more patient-tailored, higher value, and patients expect more injection options and comfort. Drug delivery will be also regulated more and more not only by regulatory statues but by safety mandates, as we can expect in Europe a wave of local anti-sharps injury regulations after last year’s new EU-wide Directive (210/32/EU).
AS: For injectable drugs approaching patent expiration over the coming five to six years, we have seen significant pharmaceutical interest in reviewing opportunities to convert to the usage of superior devices that are not accessible to generic or biosimilar competition. Such lifecycle extension strategies can strengthen the position of the brand innovator, and potentially obstruct the successful entry of a generic or biosimilar competitor.
RH: Honestly, I did not observe much of a shift. That said, I do believe companies are putting greater emphasis on leveraging existing technologies, products, and service providers as opposed to doing everything themselves, re-inventing the proverbial wheel, and/or doing things the same as they have always been done. Disposable solutions are a simple example that represents an opportunity to reduce costly validation and equipment expenditures.
SD: The market has not seen a significant change in the landscape of drug delivery post-recession. The interest in the drug device combination devices continues to be of growing interest. Perhaps we could see a big wave of products approved in a drug device combination form in the next 3-5 years
CH: No significant changes experienced.
AF: In a post-blockbuster age, the opportunity to secure worthwhile revenues with effective, high-value products, in most cases only viable if using parenteral delivery, has become a focus of attention. Naturally this has underscored the importance of injection devices and systems, with perhaps an increased focus on the cost-effective design and development of these technologies. The health economic benefit of shifting administration of therapies from the clinician to the patient has added to this pressure, further driving interest in self-injection technology.
What country/region, in your opinion, is currently leading the way in pre-filled syringe and auto-injector technology and why?
AJ: Not sure if you can pin-point it to one region/country only. I would say that Europe is in general more progressive.
AS: For the U.S., the big pharmaceutical focus for these devices has been about quality assurance for the combination product, compliance with needlestick prevention laws in healthcare facilities and the more convenient self-administration of prefilled medication by patients at home. In Europe, the prefilled market is more mature, but you should expect a strong conversion over to prefilled safety over the coming years as E.U member states introduce legislation mandating the use of needlestick prevention devices in healthcare facilities. For international regions outside of North America and Europe, price-sensitivity remains a key factor. However we expect more healthcare facilities to demand the provision of drugs in prefilled syringes given their dose accuracy, speed of dose administration and convenient disposal.
RH: The United States and Europe are the first that come to mind. They have an established infrastructure. Other countries or regions are still in the development stage, in terms of manufacturing capabilities.
SD: Most of the more established auto injector device companies have a European origin and have pioneered the path beginning in development of lancets and pens and have now evolved through innovation to the development of auto injectors. However, we are continuing to see more device companies appear in the market place (from US, EU, Israel etc) creating additional global competition.
CH: North America – due to high concentration of biopharmaceutical companies and driven by increased regulatory expectations.
AF: The major pharma/biopharma companies making use of injection technologies are truly international, with strong presence in the US and all major markets. The position with respect to technologies is, however, somewhat different. Regarding pre-filled syringe technology, the development of non-glass primary containers has been pioneered in Japan, and Japanese COP resin technology is now used by at least one western syringe manufacturer. Regarding auto injector technologies, the distinction between developer and manufacturer can sometimes be misleading, however EU based companies have played a major role in the development of a great many of the available auto injector products.
If things progress as they have the past five years, what can we expect in the next five years, with respect to the application of pre-filled syringe and auto-injector technology?
AJ: Better fit of primary container and auto-injector – more injection comfort – safe applications. We will see more adaptations to patients’ needs. I also believe that in five years there will be no bare prefilled syringes on the market as patients’ needs, safety regulations etc. will dictate drug delivery presentations.
AS: Pharmaceutical companies will begin to transition over to unique, non-commodity prefilled devices that are superior to the competition and can better enable brand differentiation and the optimization of product lifecycles. In particular, we expect the market to progressively shift from the current unsatisfactory use of ancillary safety products that areattached onto standard prefilled syringes. These stop-gap safety options, which all look and function in a similar way, significantly increase fill-finish and packaging costs, and deny any opportunities for brand differentiation. In their place, you will begin to see prefilled syringes such as our Unifill range that have fully integrated safety features fully integrated within the glass barrel. As a primary drug container that can be inserted into current fill-finish lines, minimize packaging volumes and offer superior marketing benefits, our Unifill syringes are well positioned to disrupt the current status quo.
RH: Lines will become more blurred with what is a syringe and what is a cartridge. The market will demand ‘something’ that can be placed in a drug delivery device. I would also expect plastics to play a larger role in drug delivery in the next five years, especially with biologics. Lastly, and purely from an operations perspective, I would hope we move to more standardization for auto-injectors.
SD: In the next five years, there is expected to be several more products in a disposable auto injector format. Auto-injectors are expected to become better in performance and increase in acceptance within the market place. Self-injection of viscous formulations continues to be a challenge for many drug companies and it is expected that there will be an increased focus of auto injector devices that can achieve this. While pharma companies are generally comforted by the use of standardized, off-the-shelf devices, they also ideally are looking for means to differentiate their products from their competitors’ and it is predicted the next generation auto injectors will aim to provide the benefits of market-ready devices, with an ability to adapt to the needs of particular pharma company partners.
In addition, there could be an increased interest in auto injectors in the reconstitution market addressing the lyophilized drug market which incorporate dual-chamber syringes, where the drug and diluent are provided in a single unit. Although the market is interested and looking for this type of new injection product, designing an injection device capable of reconstituting a lyophilized drug is complex; requiring consideration of the drug manufacturing processes, and seems more likely to be undertaken as a joint effort between device and drug manufacturers.
CH: Application of Quality by Design concepts to improve overall fit/ interaction of syringe with auto-injector devices.
Functionality and handling improvements for better patient compliance and product differentiation.
Improved drug compatibility through tighter manufacturing controls e.g. silicone lubricants or non-silicone lubricants.
AF: Two divergent scenarios are anticipated;
(a) Growth in the demand for smaller, less complex, lower unit cost single-use auto injectors is expected to increase. We expect to see the emergence of a ‘design consensus’ on disposable auto injector designs based around standard pre-filled syringes. A small number of ‘standard interactions’ will emerge (just as they have in disposable and reusable injector pens for insulin) and are expected to be ‘push to activate’ and ‘push-interlocked button to activate’.
(b) For treatment of chronic conditions, especially where injections are regular but infrequent, a re-usable delivery device with electronic features (reminders, alarms, precise injection control etc) can offer enhanced usability and reduced cost per dose compared to a single use product (a ~$40 device, used fortnightly over 3 years costs ~ 50 cents/shot, so significantly below the price point for current single use products). ‘EEDDs’ (Electronically Enabled Delivery Devices) are already emerging (e.g. Merck Serono’s Easipod, albeit this uses a vial rather than a prefilled syringe). So a good health economic case exists, together with enhanced usability for a well-designed product.
It is entirely possible that both the above scenarios will be fulfilled but in separate therapeutic areas.
What recent improvements/methods have been implemented to make pre-filled syringe and auto-injector technology a viable option?
AJ: Again, tighter specifications on the syringe side; availability of other materials (polymers such as CoC); flange design; also how auto-injectors ‘hold’ the syringe (on less fragile contact points).
AS: Auto-injectors and prefilled syringes are now being viewed as a critical piece of the drug-device combination product submitted in regulatory applications. Any novel claims that a device can contribute towards the combination product can add significant value to the competitive marketing of the drug. Prefilled syringes with passive, integrated safety features that can help to eliminate the risk of needlestick injuries and improve operator handling are desirable. Auto-injectors are also helping to make the administration of accurate doses more controlled and consistent than manual injections. Customizing devices to be elegant, patient centric, safe and reliable in terms of dose delivery is the future.
RH: The design–ergonomics, function, and fit with syringe–has become quite sophisticated. Just like anything else, the more you do something the better you get at it.
SD: The availability of the autoinjectors that combines being market-ready with an ability to be tailored for specific needs, without the time, cost and risk associated with full-scale device customization projects. The ability to handle glass or plastic syringes in addition to meeting the specific challenges such as viscous formulations will increase the demand of these devices.
CH: Harmonization of both worlds – drug container and delivery device: improved handling of the syringe in the AI, less stress on syringe reduces probability of breakage, tighter dimensional tolerances reducing design space for AI, consistent functionality.
AF: Regarding pre-filled syringes, attempts to improve current, glass-based products are continuing, such as better siliconisation control, improved inspection and vacuum filling as examples.
Auto injectors have benefited from many of these improvements, though problems are still being reported, in some cases attributable to the primary pack, in others related to the overall auto injector itself.
There have been a number of recent innovations in pre-filled syringe and auto injection technology. In your opinion, what advancement has had the biggest impact?
AJ: Some of the recent innovations are too new to tell whether they have a big impact on drug delivery.
AS: The prefilled syringe itself has remained largely unchanged in the last decade. In essence, you have the same suppliers,using similar materials to make a product with a design that has become commoditized. There have been some positive innovations in areas such as seal coatings or the removal of tungsten, but these have really been superficial improvements only. COC plastic materials have also failed to catch on to-date.
The same situation applies to ancillary safety products and auto-injectors that are attached onto standard prefilled syringes after filling and prior to packaging. Most share a similar look and functionality. The next big shift in the market will be the adoption of unique prefilled syringes with integrated safety features that can streamline fill-finish and packaging systems, be USP compliant, and deliver real brand equity for drugs marketed in highly competitive market sectors. We also expect there will be a convergence between prefilled syringes and auto-injectors into devices that are engineered for controlled dose administration by patients at home.
RH: I think the jury is still out on what will have the biggest impact for more recent innovations. I’m particularly interested in the retractable needles on pre-filled syringes as well as micro-infusion devices that provide the therapeutic dose through small needles in almost a patch-like look/feel.
SD: The availability of the autoinjectors that combines being market-ready with an ability to be tailored for specific needs, without the time, cost and risk associated with full-scale device customization projects. The delivery of viscous drugs (e.g. up to 100 Cps) drugs through relatively fine gauge needles will have an impact on this market.
CH: Syringe designs with increased stress resistance to prevent failure.
AF: It may be happening slowly in the US and EU, but a move away from type 1 borosilicate glass as the preferred primary container material will have an increasing impact in the near future. In Japan, 65% of all pre-filled syringes are already produced in cyclic polyolefin materials, which have been accepted there for a number of years. Development of polymeric container closure systems is a widespread activity and as one example, a polypropylene prefilled syringe is already approved and marketed in the EU by a French manufacturer.
Overall, however, there is an increasing and very welcome move towards providing real solutions and not merely to procure devices
What challenges have protein-based drugs, or biotech products in general, brought to the market recently?
AJ: Drug properties like increased viscosity are definitely a challenge for auto-injection technologies as higher (mechanical) forces are required to drive the injection. Patients also tend to desire different injection options and more control over the injection process (for example, injection and drug dispensing speed). Some of which is provided only on a limited basis by auto-injectors. We may see more developments in this direction.
AS: The customization of devices to meet the specific needs of novel therapeutic drugs can require device manufactures to develop innovative design, packaging and material solutions. Challenges include the degradation of protein-based or biotech drug products by a chemical leached from the packaging component. Another factor is the adsorption of excipient or protein-based product to solid material of packaging components. Finally, we recognize that the higher viscosity of drugs due to their molecular shape, size, self-crowding and electrostatic intermolecular interactions require the development of complex biotech drug-device combination products.
RH: Sensitivities and material compatibilities – known and unknown – which could include cleaning agents/residual, stainless steel, silicone, glass, etc. is certainly one of the challenges. I don’t envy the process and formulation development scientists that need to dial this all in.
SD: Protein based drugs, when concentrated to reduce volume, can be viscous in nature. In addition proteins have a tendency to react with the silicone and form agglomerates which cause problems with the assay of the drug. This has resulted in the development of either syringes with low or no silicone to handle these compounds.
In addition variations have been created that have baked on silicone on a syringe to minimize the amount of silicone available for interaction. The distribution of the silicone inside the syringe should be uniform to generate a smooth movement for the plunger stopper. This is a critical step when syringes are combined with an auto-injector.
Some protein therapeutics are also known to be sensitive to tungsten. Manufacturers have developed several ways to reduce or eliminate tungsten in the manufacture of glass syringes. These syringes are made from polymers such as cyclo olefin copolymer (COC) or cyclo-olefin polymer (COP).
Together with several of these new innovations and breakthroughs around the syringe and the auto injector, ultimately, the end user will be able to have the option of easy to use, convenient and customized therapeutic treatments.
CH: In general these products may have a higher sensitivity for interaction with primary packaging materials such as glass, tungsten, silicone, adhesive and elastomers.
AF: The sensitivity of protein-based and bio-derived drugs to tungsten residues and silicone oil is now a recognized issue with traditional glass-bodied pre-filled syringes.
The higher viscosities associated with many biologic products demand higher syringe plunger forces, which can became a problem in auto-injector design; ‘just adding a stronger delivery spring’ to ensure full dose delivery is often not as easy as it sounds, and syringe breakage can be a problem. This is exacerbated by the reduced dimensional control associated with a hot-formed glass syringe barrel and the variability of barrel/plunger lubrication. (These issues are largely absent with injection moulded syringe barrels)
This article was printed in the April 2011 issue of American Pharmaceutical Review - Volume 14, Issue 3. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.