Please tell us about some recent advances in drug delivery.
David Lyon: Demand is increasing for oral delivery of biomolecules, such as vaccines, peptides and proteins, especially for the treatment of local gut diseases, including irritable bowel disease (IBD). At Capsugel Dosage Form Solutions, we continue to invest in core technologies such as hard shell capsule and spray dry dispersion formulation approaches to biomolecules. Following are two examples of recent advances.
- Enteric capsule drug delivery technology represents a new, faster and easier means for oral delivery of labile entities such as peptides, nucleotides and vaccines. Intrinsic enteric functionality in the capsule shell can enable oral delivery of such actives that require gastric protection but are sensitive to degradation during conventional processing due to temperature or oxygen-exposure associated with conventional processes. We are working with a number of clients evaluating large molecule delivery with this new technology.
- Solid-state formulations, using spray-drying (SD) technology, represent a potential solution for shipping biologic drug product intermediate or final drug product without the need for cold-chain storage. SD technology is used to modify drug properties by adjusting excipient composition, atomization and drying conditions, and is easily scalable. Our current work includes SD adaptation to a wide variety of biotherapeutics, inclusive of monoclonal antibodies, vaccines, proteins and peptides.
Elliott Berger: Catalent has invested in developing technologies focused on enhancing solubility and bioavailability of drugs, as these are key challenges to successful drug delivery. There are many approaches in this field, including chemical modification, particle size reduction, and hot melt extrusion to produce stable, amorphous dispersions, and lipid-based formulations. With over 80 years of softgel formulation experience with RP Scherer softgel technology, recent innovations include OptiShell™ Technology, a soft, gelatin-free encapsulation which allows for higher melting point fill formulations, and is also capable of modifying the release of poorly soluble and/or poorly permeable drug compounds.
In another area, Catalent has also recently expanded its ADVASEPT™ technology platform, providing glass-free advanced aseptic filling for injectable drugs. With the increasing number of biologics and macromolecular therapies coming to the market, where injection is, as yet, the only viable route of administration, ADVASEPT technology offers security to drug developers by reducing the risks of particle and microbial contamination associated with traditional glass vial fill-finish processes.
Mark Mitchnick: At Particle Sciences we focus on technologies that are commercial ready. Over the past few years several technologies have really matured. By this I mean they have become mainstream even though they have generally been available for some time. These include drug nano-crystals, solid lipid nanoparticles and implants. For each of these, we are seeing tremendous interest as first line technologies where in the past, they would have been a “last resort”. At PSI we have put our resources into fully enabling these technologies from bench to production for all types of APIs.
Thomas Otto: By the very nature of the industry, there are always advances being made or under development in the field of drug delivery technology and devices. In fact, there is perhaps no time where this is more true than the present. Today, when outsourcing their drug product manufacturing, bio/pharmaceutical companies expect a wide-service offering from their strategic partners to meet their needs, including the latest in manufacturing technology that can help them to reach their targets. Often, this means fulfilling mutually agreed upon key performance indicators in regards to API yield and cost optimization; and at the same time, improved drug product quality and a high-degree of flexibility.
Therefore, to be successful and a trusted partner of the industry, for a CDMO to meet or exceed these indicators is important. And here, flexibility is one central property.
We know from our experience that there are a variety of additional success factors that enter this equation. These include a continuous focus on increased automation in production which is critical in meeting the ever-stringent regulatory requirements. That means minimizing human intervention which, in turn, minimizes the risk of contamination and enables high drug product quality.
At Vetter, we have achieved this level of quality through the use of RABS technology. RABS-operated cleanrooms are also able to efficiently meet the varying sizes of differing batches through quick product changeovers. To minimize loss of valuable API, innovative equipment is applied. For example, when manufacturing various products with differing needs on a single filling line, applying a high level of disposable technology is often appropriate, whereas the use of stainless steel equipment might be more promising in other cases.
Additionally, CDMOs can contribute to establish the conditions for applying new and innovative primary packaging materials such as polymer syringes to enable more product-specific handling. Polymer has been very effective in solving problems associated with API/glass barrel interactions.
Aside from the actual technology and devices themselves, also ‘decisive processes’ in the field of quality and technology such as Quality by Design, or Process Analytical Technology seems to be appropriate, to mention just two examples.
Eric Resnick: Some of the most exciting innovations in drug delivery are in connected health. Historically, the use of connectivity in drug delivery has been restricted by access to an appropriate infrastructure. Now, with electronically integrated drug delivery systems and new mechanisms to generate, capture and store data, there are numerous opportunities for pharmaceutical companies to provide patients with truly integrated and connected systems.
Within this ecosystem, the focus of companies like West and The Tech Group, our global contract manufacturing solutions provider, is on easy-to-use technologies that can help boost patient adherence while simultaneously capturing and transmitting drug delivery data. Among pharmaceutical manufacturers, we are seeing growing demand for drug delivery systems that can capture data from a drug delivery event, such as administration of an injection, and link that data to tools that can record this information for patients, physicians and payers.
This data can provide valuable insights into patient behaviors. For example, West and HealthPrize, a leader in patient engagement and medication adherence solutions, are collaborating on a connected health offering that is designed to help improve and reward medication adherence with unique gamification technologies. The offering integrates HealthPrize’s Software-as-a-Service medication adherence and patient engagement platform into injectable drug delivery systems, providing pharmaceutical companies and their patients with an end-to-end connected health solution. By offering education and rewards-based self-injection systems, West and HealthPrize aim to motivate patients, help boost medication adherence and improve patient outcomes.
Have you noticed any trends favoring one type of delivery method over another?
Lyon: While injectable delivery of biotherapeutics is very common, oral delivery of proteins, when applicable, is increasing due to technological advances, driven by the inherent convenience and patient acceptability of oral dosing.
We are also seeing increased interest in the pulmonary route for local and systemic delivery across a wider range of therapeutic areas, such as infectious diseases and genetic disorders.
Additionally, within the oral solid dose category, we see continued growth and preference for multiparticulate approaches due to interest in fixed dose combinations and increased ease of swallowing for specialized pediatric and geriatric populations.
Berger: Oral delivery is often favored because of patient preference, and ease of administration and manufacture. However, a high proportion of drugs in development are more challenging to deliver, and increasingly sophisticated technologies are being employed to ensure doses are easy to swallow, avoid food effect, and achieve the desired bioavailability profile; without imposing an excessive pill burden. The right adherence level also helps ensure clinical efficacy and increasingly drives reimbursement. Biologics are viable for oral delivery as injections don’t offer these advantages. Innovation in oral dose forms, including multi-core tablet technologies, oral fast dissolve approaches, functional coatings and new softgel formulation techniques are emerging to improve delivery options.
Inhaled dose forms are increasingly in demand as more therapies seek to use the lungs as the clinical delivery point for systemic effect. Prevalence and diagnosis of respiratory disease in emerging markets will continue to drive the development of inhalable therapies too.
In sterile delivery there is a trend towards safer, patient friendly glass- and needle-free delivery technologies, based on Blow-Fill-Seal technologies like ADVASEPT™ or on novel medical devices. Much technical innovation is going on in this area, partially driven by biologics development, emerging market needs and the trend toward preservative-free formulations.
Mitchnick: Yes, given that many if not most API’s have bioavailability challenges, we see a growing interest in nanoparticles and implants. Not only do both offer performance advantages but each has unique intellectual property potential making them very attractive to our clients.
Resnick: Because patient preferences for drug administration differ, it is increasingly clear that there is no “one-size-fits-all” delivery system solution. With the rise in home-based administration for the treatment of chronic conditions, patients are becoming more hands-on in their treatment. When self-injecting medicine, some patients feel more confident using a prefilled syringe with a simple needle-safety device. Others may prefer a wearable patch injector where the needle cannot be seen. At West, we provide a portfolio of self-injection systems for that very reason.
Regarding materials within the devices themselves, we’re seeing more pharma manufacturers exploring alternatives to glass. Traditionally, glass has been used as a primary material due to a variety of characteristics that enable safe and efficient drug storage. However, there are risks associated with glass, including delamination, breakage and chemical incompatibility with the drug product. Novel plastic systems have proven to be alternatives for maintaining the strength, quality and purity of many injectable drug products. For example, high-quality polymers such as West’s Daikyo Crystal Zenith® (CZ) can mitigate many of the issues with glass by reducing the risk of breakage, cracking and container/drug interaction. The ConfiDose® auto-injector system and SmartDose® electronic wearable injector both feature CZ primary containers.
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 today’s innovative drug products.
Are there specific categories or types of drugs that pose more demanding drug delivery challenges? If so, what are they, and how do you approach these challenges?
Lyon: There are increasing efforts to deliver a range of sensitive molecules, including vaccines, nucleotides and peptides, and larger biotherapeutic molecules via oral and pulmonary delivery. These molecules are often labile in the gastric environment or in the presence of intestinal enzymes.
For oral delivery, Capsugel/Bend Research has developed intrinsically enteric capsule drug delivery technology to protect biomolecules from the gastric milieu in addition to protein-coating and spray drying capabilities to allow rapid gastric transport.
We are also exploring pulmonary delivery to treat systemic diseases (e.g. influenza, pain management and gene therapies) with the potential for improved bioavailability of drugs that are otherwise poorly absorbed within the gastrointestinal tract. Particle engineering advances using spray dry technology has proven successful in optimizing particle size distribution for effective drug delivery to the lung using Dry Powder Inhalers (DPIs).
Berger: Each drug is, by its very nature, unique and comes with its own challenges, however solubility is usually by far the greatest challenge. It is estimated that up to 70% of all therapies in development are poorly water soluble, and Catalent has responded to this challenge by providing a wide range of tools to optimize formulations and overcome this. Its screening platform, Optiform® Technology, can assist in identifying the most stable crystalline form of a molecule and aid in-silico preformulation as well as salt, co-crystal, and crystal form selection.
With its wide range of final dosage forms, including softgels and the advanced OptiShell™ capsules, coupled with formulation technology platforms including hot melt extrusion and particle size engineering, Catalent’s toolkit offers a wide range of solutions for each individual drug delivery challenge.
Mitchnick: A thorough answer to this question is well beyond the scope of this short survey but, in general, many of the APIs/drug products we see fall into one or more of the following: highly potent, biologics, sterile, limited solubility and sustained delivery. We approach these demands with a variety of formulation platforms ranging from nanoparticles to drug eluting devices. For clinical supplies, PSI has an extensive cGMP capability including dedicated high potency and sterile suites.
Otto: In the biologics sector where the active ingredients of the compounds are large and very complex molecules, their manufacture is extremely challenging. To do so demands a vast degree of experience and a substantial degree of process expertise. Biologics react with far greater sensitivity to environmental influences such as light and heat than do other substances. Thus, the correct product-related production processes need to be designed and implemented. For example, using the correct pumps in the filling process is critical. Also, for manufacturers it is important to have a significant knowledge of packing materials and components. As one example, biologics often react negatively to the silicon that is required inside a glass syringe for proper plunger operation, or to the chemical composition of the stopper.
As biologic compounds often are sensitive to these materials and other environmental influences, the technology of lyophilization is an option for protection. This is why in the area of aseptic manufacturing Vetter is focused on offering appropriate solutions that include lyophilizing drug substances. This first requires having in place adequate production lines with lyophilizers that perform this production step. Along with the customer, we then select the best-suited primary packaging material, followed by developing and implementing the most effective production processes such as the correct lyophilization cycle.
The lyophilization process can be a suitable solution for providing stability to a drug substance for a longer period of time. However, the challenge is preparing them for administration since the drug substance itself needs to be dissolved in a diluent prior to use. If the lyophilized substance is in a conventional vial, for example, several steps will be necessary. Even for seasoned healthcare professional, this process is not always easy and therefore, limits the market opportunities for such device combinations, especially in the important home healthcare market. This is why more user-friendly systems are those that make the dissolution step in the process even easier. The best suitable form available today is, in our opinion, one where the lyophilized substance and the diluent are both contained within the same system, which means a multi-chamber system. In a dual-chamber syringe for example, the aseptically filled freeze-dried drug resides in one chamber and the diluent in the other. Engaging the plunger simply mixes the two, and enables fast and safe administration.
Resnick: Biologics are gaining traction because of attributes that allow for self-administration. However, these sensitive drug products present multiple challenges that require alternative packaging and new approaches to containment and delivery. Some biologic drug products do not react well with glass; others may be sensitive to silicone oil or tungsten (materials often used in traditional drug packaging and delivery systems). Additionally, some large molecule biologics are highly viscous requiring controlled delivery over time.
These concerns are giving rise to advanced injection systems that have evolved to meet the needs of biologic formulations. For example, the SmartDose® electronic wearable injector can deliver higher dose volumes by controlled injection of the drug over a period of time. These unique systems with larger fill volumes and tighter dimensional tolerance can be used, while still remaining compatible with established manufacturer filling technologies. The use of high-quality polymers adds value to sensitive biologics through enhanced cleanliness and decreased interaction with the biologic drug product.
Looking ahead, can you tell us about any emerging drug delivery technologies that will have an impact on healthcare and patient compliance?
Lyon: Converting parenteral routes of administration to either oral solid dosing or pulmonary delivery, where appropriate, will likely result in improved patient compliance. Converting protein injections to oral can further enable certain drug therapies in developing nations where cold chain storage is a particular challenge.
Berger: Recent advancements in lipid-based formulations have increased the viability of oral dosing of macromolecules. This is just one option that may reduce reliance upon injection of such therapies. Reducing invasive techniques of delivery will help to increase patient compliance and therapeutic efficacy, and research groups set up by the Catalent Advanced Drug Delivery Institute are exploring new and emerging technologies in areas including inhaled formulations to further reduce the use of injection.
Catalent is also undertaking pioneering work in the oral delivery of vaccines and commenced proof-of-concept research using the influenza vaccine, which is looking very promising. Using its fast-dissolve technology, Zydis® Bio, the aim is to deliver the vaccine sublingually and bypass the acidic environment of the stomach which generally destroys vaccines. The technology has been used to deliver an allergy vaccine, however the difference in triggering an immune response - rather than immune tolerance with allergens – leads to greater challenges, so research is still at an early stage. The potential advantages of being able to produce a non-injectable, room temperature-stable vaccine delivery system could revolutionise the field, especially in developing countries, where cold chain storage and lower numbers of trained healthcare practitioners are huge barriers to mass vaccination.
Mitchnick: We believe the greatest impact is going to be in the areas of biologics and sustained release. For drug delivery related to biologics we see innovation in combining large and small molecules. Our SATx® technology for instance enables the rapid development of target therapies. For both large and small molecules, compliance is a major issue and here implants are playing an increasing role. Many of the new drugs are insoluble and highly potent making them ideal for an implant strategy where years or therapeutic can be delivered in one simple step. PSI is the leading CDMO for implant development and judging by our project list, interest is growing by double digits.
Otto: No doubt, one of the greatest challenges facing the industry today is drug counterfeiting. This is a problem that is growing in scope and costing the industry enormous sums of money. Even more important, drug counterfeiting puts patients’ lives at risk.
As the number of counterfeit drugs continues to escalate, regulatory authorities around the world are increasingly demanding the clear identification of products through a process known as ‘serialization’. With serialization, the smallest packaging unit is marked with a singleuse identification number. This serialization technology is undergoing implementation worldwide over the next few years to combat counterfeiting and to keep patients safe, contributing to an overall secure drug supply chain.
Another challenge facing the industry with high business impact is the continuous growth of the homecare sector mentioned earlier. Consistent with an aging patient population is the increased need for convenient and safe self-administration products. For example, patients with chronic diseases such as multiple sclerosis or rheumatoid arthritis are demanding the option of user-friendly devices. Such options lessen their reliance on hospitals and healthcare workers, making their daily lives more convenient and independent overall.
Resnick: Biologics are gaining traction because of attributes that allow for self-administration. However, these sensitive drug products present multiple challenges that require alternative packaging and new approaches to containment and delivery. Some biologic drug products do not react well with glass; others may be sensitive to silicone oil or tungsten (materials often used in traditional drug packaging and delivery systems). Additionally, some large molecule biologics are highly viscous requiring controlled delivery over time.
These concerns are giving rise to advanced injection systems that have evolved to meet the needs of biologic formulations. For example, the SmartDose® electronic wearable injector can deliver higher dose volumes by controlled injection of the drug over a period of time. These unique systems with larger fill volumes and tighter dimensional tolerance can be used, while still remaining compatible with established manufacturer filling technologies. The use of high-quality polymers adds value to sensitive biologics through enhanced cleanliness and decreased interaction with the biologic drug product.