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.
Self-administration
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.
Wearable devices
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.”
Drug packaging
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 devices
BioPharm: 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 engineering
BioPharm: 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.