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Industry experts spoke to BioPharm International about the key considerations in the development of a drug-delivery device for a biologic drug, the importance of human factors engineering, the advantages of prefilled syringes, and the challenges in the manufacture of these devices.
The personalized medicines era is shifting the focus of pharmaceutical development and manufacturing activities from small molecules to biologic drug products. The formulation of these complex macromolecules, however, is not as straightforward as their small-molecule counterparts. The high patient doses required for biologic therapeutics, for example, present significant drug-delivery challenges, according to Johann Stasny, director, Global Sales Development, Bioavailability Enhancement & Custom API, Merck Millipore KGaA, Darmstadt, Germany. “On average, a dose of 0.1 mg to 3 mg per kg of patient body weight is required,” Stasny notes. Because of their nature, biopharmaceuticals are not easy to deliver via the oral route, explains Kate Hudson-Farmer, market insight strategist, Drug Delivery, Cambridge Consultants. A large proportion of these drugs are currently injected using intravenous infusion in the hospital, or increasingly in the home, she says.
Most biologic products for parenteral administration are freeze-dried in vials to help maintain drug stability and increase shelf life. But interest is growing in the development of liquid formulations in prefilled syringes and autoinjectors, which offer convenience and ease of administration in a home setting. Stasny observes a shift for certain biologics-especially those indicated for chronic conditions such as inflammatory diseases-toward prefilled syringes for subcutaneous administration. “This delivery method has better patient compliance and efficiency in cases where a high concentration of the drug is required due to the low dosage volume that can be administered,” he says.
“The trend in self-administration continues to grow,” Hudson-Farmer notes. Claus Feussner, PhD, senior vice-president, Development Service, Vetter, attributes it to the expanding home healthcare market, which he says is a direct reflection of a constantly aging population, particularly in the more established countries. And as a means to control costs and avoid expensive therapies in either a hospital or a doctor’s office, healthcare authorities are putting pressure on the industry to develop medicines that patients can self-administer in a private setting, according to Feussner.
Hudson-Farmer, nonetheless, points out that self-administration has its challenges. Patients require training and education to ensure that these drug-delivery systems are used correctly. “But this is not the only problem,” she asserts, “because self-injection, whichever way you look at it, is not a pleasant thing to have to do, and adherence and compliance to such drugs is often a problem.”
In addition, drug companies are faced with the challenge of having to deliver larger volumes of biologic formulations, often beyond the capacity allowed by a syringe or an autoinjector. “This is in part due to the trend towards less frequent injection and in part, to drug formulation issues,” says Hudson-Farmer. Patch pumps or on-body injectors that can deliver the drugs in a subcutaneous manner are being developed, she adds. “There have been some interesting advances in this area including the pre-timed, worn-on-body injector that Amgen launched for its Neulasta drug using Omnipod’s on-body injector,” Hudson-Farmer highlights.
Andy Fry, founder of Team Consulting, notes that wearable devices, which provide an alternative to prefilled syringes and autoinjectors, are attracting a great deal of interest. “A wearable device allows drug delivery over a significantly longer period than the typical 10- to 20-second window associated with an autoinjector. Because of this feature, a wearable device can enable large-volume doses, or high-viscosity formulations, or even larger-volume payloads at high viscosity, to be delivered at acceptable levels of patient discomfort,” he explains. “There has also been renewed interest in all-in-one dual-chamber devices, which aim to take the fiddle and complication out of reconstitution of lyophilized products for self-injection while avoiding the necessity of cold-chain transportation and storage.”
Graham Reynolds, vice-president of marketing and communications, Delivery Systems, West Pharmaceutical Services, sees an increased need for innovative and effective drug packaging and delivery of biopharmaceuticals. “Additionally, as biologics begin to come off patent, demand for delivery systems that can safely contain and deliver biosimilars should continue to rise, especially as easy-to-use delivery systems can help differentiate drug products,” he says.
The industry also continues to seek alternatives to glass, such as polymer-based systems, for drug packaging and delivery systems, according to Reynolds. “This is particularly true for biologics, which can be sensitive to their containers,” he observes. “Glass-related risks, such as delamination, breakage, and chemical incompatibility with the drug product do not exist with the newer polymer offerings. These platforms offer a range of options for dose volume and injection time and are designed to help improve patient compliance and outcomes, while meeting the challenges of injectable drug products.”
Biologics are sensitive drug products, explains Reynolds, emphasizing the need for ultra-clean packaging components to ensure that there is a low risk of contamination or particulate. “Manufacturers and regulators are demanding that drug containment and delivery systems have the highest levels of quality possible to maintain the purity of these sensitive medicines,” he asserts.
Excipients and process chemicals
According to Stasny, a holistic approach is required to better understand the full process by which the formulation of a biologic drug product is implemented. “Biologic processing, in general, is evolving to a more efficient platform,” he says. “High-titer bioreactor production, higher capacity chromatographic systems, and continuous processing strategies will create additional stresses on biologic products during processing to achieve the final formulation.”
Stasny explains that higher concentrations of biologics throughout the purification process and into the final formulation create greater chances of intermolecular interaction, thereby leading to higher potential for aggregation. “Once the final formulation has been optimized and assessed, challenges such as viscosity derived from high-concentration systems have equivalent impact on the ability to process, formulate, and deliver the biologic drug,” he continues. “Formulation design through appropriate selection of excipients and process chemistry may be employed to mitigate both aggregation and viscosity challenges both in the final dosage form and upstream into the process to improve yield and efficiency. Because aggregates have a considerable impact on immunogenicity, minimization of aggregation potential through appropriate process and formulation design will provide an additional benefit.”
In addition, the qualification of the excipients and process chemicals used are important, says Stasny, not only to meet regulatory requirements, but also because the quality attributes can reduce oxidative contaminants. “Identification and control of levels of reducing sugars, peroxides, aldehydes, elemental impurities, and other detrimental contaminants in both process chemicals and excipients will reduce oxidative potential, leading to improved stability,” says Stasny.
In the following roundtable discussion, experts spoke to BioPharm International about the key considerations in the development of a drug-delivery device for a biologic drug, the importance of human factors engineering, the advantages of prefilled syringes, and the challenges involved in the manufacture of these devices. Participants were: Hudson-Farmer from Cambridge Consultants; Reynolds from West Pharmaceutical Services; Feussner from Vetter; and Fry and Julian Dixon, director of human factors, both from Team Consulting.
Drug-delivery devicesBioPharm: How do you develop a successful drug-delivery device for a biologic drug?
Hudson-Farmer (Cambridge Consultants): Success is a combination of many factors. Most of the formulation issues do not affect the development of conventional devices like auto-injectors, as stability is governed by compatibility with the primary pack (usually a prefilled syringe) and not the rest of the device. However, with the move toward self-administration, resolving formulation issues such as stability without the appropriate consideration of usability challenges success. Lyophilization, for example, is a good way to stabilize a drug, but it increases preparation complexity for the patient due to the need to reconstitute the drug prior to injection.
Self-injection opens up a variety of delivery opportunities compared with conventional oral delivery of drugs. Ensuring there is some degree of flexibility for the patients using these devices, and the healthcare workers assisting and advising the patients, is key. There will be distinct needs for certain patient groups that vary from therapeutic area to therapeutic area. Designing the device of choice for a rheumatoid arthritis patient, for example, may differ significantly to a patient who needs to use it as a rescue device for allergies.
There are also differences in needs within a therapeutic area. Some may want a simple device that works quickly, and they can forget about the condition they have as soon as injection is completed. Others may be more interested in understanding their disease and managing it closely, and could benefit from more interactive features, such as those offered from connected health add-ons.
Product differentiation using the device element of the therapy can give the pharmaceutical company a competitive edge, but there has to be a balance in terms of the increased cost and complexity of sophisticated device offerings. The device can present technical formulation challenges besides the challenges related to the optimization of the device configuration, such as the need for new primary packaging materials. Keeping certain aspects consistent, such as primary packaging, is important so that new regulatory demands are not placed on the drug. A device platform that could be altered to improve patient experience, without having to take the whole device through trials for every alteration, would be very appealing.
Fry (Team Consulting): Easy-to-use dual chamber reconstitution systems can side-step stability issues with a configuration that is relatively easy to use. Protein aggregation is usually associated with silicone oil used to reduce stopper friction; therefore, steps to reduce or even eliminate silicone oil are worth exploring. These steps may include much closer control of the siliconization process, using low-friction stoppers, or cyclic polyolefin syringes that require no silicone lubricant. Wearable devices have the capacity to manage both high volumes and high viscosities, so a wearable, dual-chamber device may well have the potential to tick several boxes at once.
When it comes to developing a successful drug-delivery device for a biologic drug, it is always better to start early. All too often, device developers are approached when the biopharmaceutical company has already made all the formulation decisions and presents a ‘fait accompli’ formulation with little or no room to explore potentially worthwhile options, which might have existed had some dialogue taken place earlier. Two major issues that are sometimes left too late are device usability and manufacturability. These issues must be part of the design thinking and the development process from the earliest point possible.
Human factors engineeringBioPharm: Can you elaborate on the importance of human factors engineering (HFE)?
Hudson-Farmer (Cambridge Consultants): The importance of HFE has increased dramatically over the past few years, and its impact on human safety has resulted in greater attention from the regulators, particularly FDA. The concern is increased further by the move towards self-administration, which increases the risk of usage error. FDA has introduced guidance (1) that calls for HFE to be integrated into combination product development as part of the risk-management process. A combination of analytical methods and observational studies is recommended to identify causes of error and assess and propose mitigations. A final validation study is then conducted to show that the usability has been optimized.
The use of HFE, although still in its early days, can potentially reduce usage error and allow for safer products. A possibly more exciting situation will be to use HFE to support better patient engagement and address the wider issue of non-adherence. In this case, the issue moves from making devices that people are able to use to making devices that people want to use.
Dixon (Team Consulting): HFE is important in this arena for two different reasons. Firstly, it is a regulatory requirement to demonstrate that HFE has been considered throughout development. The regulatory bodies, particularly FDA, are correctly stressing that drug-delivery devices need to be safe and effective in the hands of their users. It is important, therefore, that an appropriate HFE plan has been followed. Failure to do so, even if the drug-delivery device is well designed, represents a significant regulatory risk, and the product may not be approved as a result.
Secondly, a balanced consideration of HFE throughout development will ensure that the drug-delivery system is as good as it can be. The drug-delivery field has been late to embrace user-centric and human factors principles. There is now a general agreement on their importance. The best way to develop drug-delivery devices is to have a well-integrated team of technologists, formulators, engineers, designers, and human factors experts. Another key takeaway is that HFE is important because failure to consider its inputs to design and development will result in a suboptimal product.
Prefilled syringesBioPharm: Do you see an increasing demand for prefilled syringes?
Feussner (Vetter): The drug-development model today is far more intricate compared with some years ago, created by factors that include a higher complexity of new compounds in development. Companies hoping to succeed must make innovation central to their drug-development business approach, which includes looking outside traditional methods of drug delivery in clinical phases.
The global prefilled-syringe market is expected to show continued positive growth due to rapidly increasing development of biologic drugs. There is also a rising demand for more user-friendly administration, starting in the clinical phase and continuing in the commercialization of a drug. With more biologics competing in the same therapeutic space, launching a drug product in a syringe can help set it apart from the competition.
Reynolds (West): Prefilled syringes remain a container of choice for many injectable drugs, especially for biologics, and there’s no indication that utilization will decline anytime soon. Because the prefilled syringe delivery system has so many formats using the same primary container, delivery can be customized based on need. For example, home administration is often best suited for autoinjectors, which can provide fully automated needle insertion, dose delivery, and needle retraction. For hospital-based administration, needlestick prevention systems can be essential to meet the requirements of legislation on safety and protect healthcare workers. In all cases, prefilled syringes are designed to meet the needs of not only the pharma/biotech companies, but also the patient.
BioPharm: What are the advantages of prefilled syringes for delivering biologic formulations compared to other injection technologies?
Reynolds (West): From a patient standpoint, prefilled syringes facilitate accurate, pre-measured doses, hence, eliminating the risk of over- or under-medication. Another advantage is that prefilled syringes in autoinjector formats allow patients to administer the drug from home, as opposed to visiting a healthcare provider, which reduces the amount of time spent in transit and eliminates a burden for patients with weakened conditions.
Accessories such as extended finger flanges, needle shield removal systems, or ergonomic plunger rods can be valuable in addressing patient needs and can accommodate biologic drugs with higher viscosities or higher dose volumes. These advancements continue to position prefilled syringes as a more viable option for a wider range of patients.
Feussner (Vetter): The key to the rapidly changing healthcare market is offering solutions for the need of patient-friendly systems. Instead of undertaking several preparation steps prior to administration, the prefilled syringe, also known as an all-in-one system, provides a number of advantages in the clinical stage as well as in the day-to-day operations of a product already launched. These advantages include:
BioPharm: What are the challenges associated with prefilled syringes?
Feussner (Vetter): Creating easy-to-apply systems often means a more complicated production process at the outset. A syringe system is a complicated instrument, consisting of a number of individual components. The correct conjunction and interaction of each module is decisive. For example, consider that administering a drug using a syringe requires a plunger rod that operates in concert with the other components, especially the glass barrel itself. To achieve this, a small coat of silicone is applied at the inner surface of the glass barrel. Finding the correct amount of silicone to enable the correct movement of the plunger rod, while avoiding any form of interaction between the silicone and the drug substance coming into contact with each other, is a significant challenge.
Also, because the glass barrel of a syringe by nature is more complex than the glass barrel of a vial, there exists a higher risk for mistakes or damage to the barrel such as glass scratches, or even glass breakage. This is why all the partners in the supply chain have been focused individually and collectively on this issue for a number of years already. All players, from the glass manufacturers and the prefilled syringes manufacturers to the bio/pharmaceutical companies and their CDMOs, are striving to achieve optimal results for the benefit of the patient.
Reynolds (West): Biologic molecules tend to be sensitive to products commonly found in traditional glass prefillable syringe systems, such as metal ions and silicone oil, substances that may affect the drug product’s efficacy and a delivery system’s performance. On a macro level, one of the biggest challenges is understanding the interactions between all elements of the drug-delivery system. This extends beyond just the drug, container, and delivery device, but also takes into consideration the most important part of the equation-the patient. Understanding all key elements of a drug-delivery system provides the cornerstone that enables this system to achieve the goals of encouraging adherence in the home-care environment. Drug manufacturers should seek a partner that can apply proprietary technologies, manufacturing excellence, and patient understanding to their drug products and the products’ packaging, delivery, and administration systems.
BioPharm: What testing do you have to carry out to ensure sterility and stability of the formulation as well as compatibility between the prefilled syringe and drug?
Reynolds (West): It is important to implement early testing for extractables and leachables. Complex chemicals that may be present in drug container and component materials can potentially interact with and affect the efficacy of the injectable drug products. Extractables migrate from packaging or other components and are found under exaggerated conditions, while leachables migrate from packaging or other components into drug products under normal conditions.
It is crucial to detail all of the materials that come into direct contact with a drug product during every phase to reduce the risk of contamination. Extractables and leachables testing is recommended even if containers or components meet compendial suitability tests, and should be carried out as part of the qualification for the container and its components.
Such testing includes liquid chromatography/mass spectrometry (LC–MS), gas chromatography/mass spectrometry (GC–MS), inductively coupled plasma (ICP), and ion chromatography (IC). The results will be a materials profile that offers a clear picture of components that come into direct contact with the product. Early extractable and leachable testing offers the opportunity to improve understanding of compatibility while reducing risk and expediting total development and launch timelines.
Feussner (Vetter): For sterile injectables, there is a standard set of analytical tests needed to prove the sterility of the product for formal market release. It starts with quality control of the incoming components. For the drug filling production step, environmental monitoring of the surroundings and in process controls of the drug solution are usually carried out, including bioburden during filtration steps, sterility testing, and bacterial endotoxin testing. Furthermore, syringes are tested for integrity of closure through a number of qualified methods.
The analytics used to assess stability of the drug are specific to the type of compound itself. Testing can be split into the standard chemical tests (e.g., pH, osmolality appearance, and residual moisture) and compound-specific characterization tests.
Drug-stability testing is carried out to test for tolerance to syringe contact surface substances, such as silicone. The amount of silicone is tested using Fourier transform infrared spectroscopy or atomic absorption spectroscopy. In addition, the distribution of the silicone in the syringe can also be examined.
Beyond silicone contact sensitivity, protein-based compounds can also be sensitive to a wide range of other factors, which include reactions to uncoated rubber or to the glue used to fix a staked needle. A number of analytics can be carried out to look for possible degradation products and the generation of denatured proteins.
1. FDA, Draft Guidance for Industry and Food and Drug Administration Staff, Applying Human Factors and Usability Engineering to Optimize Medical Device Design (Rockville, MD, November 2014).
Article DetailsBioPharm International
Vol. 28, No. 8
Citation: When referring to this article, please cite it as A. Siew, "Drug-Delivery Systems for Biopharmaceuticals," BioPharm International 28 (8) 14–19 (2015).