What are some current critical industry issues that have made drug delivery such a hot topic?
Yihong Qiu, Ph.D., Sr. Research Fellow, Drug Products, Operations Science and Technology, AbbVie: Poor water solubility continues to be one of the major challenges facing the industry in terms of oral drug delivery. Up to 90% of current candidates from the discovery small molecule pipeline across many therapeutic areas, such as oncology, infectious or rare diseases, are having solubility/dissolution problems. Many of these compounds are extremely insoluble. Twenty to 30 years ago, we thought of poorly soluble compounds in terms of 100 μg/mL, and today we are working on a few μg/mL or even ng/mL solubility. It causes tremendous difficulties in early preclinical and safety studies that require high exposure in animal models. It also presents different types of significant challenges when designing a stable and bioavailable commercial product. The drugs we are developing and manufacturing in recent years are even less soluble than KALETRA® which was approved in 2000. Over the years, AbbVie has been conducting research at the forefront to dig more deeply into the fundamental aspects of solubility/ dissolution and drug delivery technologies for increasing oral absorption.
Dr. Donald Kelemen, Head of Corporate Business Development, ABITEC: The relevance and importance of drug delivery solutions across the pharmaceutical sector cannot be over emphasized. Novel drug delivery systems offer impactful solutions for developing new or improving existing therapeutics to address a broad range of clinical and patient objectives including bioavailability enhancement, improved safety, decreased toxicity and improved patient compliance.
Cornell Stamoran, Vice President of Corporate Strategy, Catalent Pharma Solutions: The foremost driving issue is the increasing complexity of compounds in the pipeline. The average small molecule compound is less bioavailable, often combined with other technical or clinical formulation challenges, such as targeted complex release profiles for therapeutic efficacy. Large molecule proteins pose other challenges, such as target site administration/delivery, large volume requirements driving less desirable infusion delivery, and the frequent use of non-standard delivery devices. And new treatment modalities, such as cell and gene therapy, mRNA, and RNAi will require further drug delivery innovation still.
Compounding the increase in molecular complexity is the ever-increasing need for differentiated clinical outcomes, to gain market access and reimbursement, written prescriptions and patient interest. There’s a long history showing that drug delivery done right – the right molecule form, the right formulation, the right dose form and device – can enable products to deliver better outcomes for patients, and in the market.
David Elder, Independent CMC Consultant: The adverse impact of highthroughput and combinatorial chemistry has resulted in molecular weight inflation of new chemical entities (NCEs), resulting in increased lipophilicity and decreased aqueous solubility. Historically, small biopharma companies have not adequately invested in formulation development/optimization for these type of molecules, believing that simple, cheap formulations that enable fast development were the optimal approach. However, if the absorption is solubility-limited then without appropriate formulation intervention the company will not be able to adequately explore the pharmacology in man. The development classification system (DCS) enables companies to rapidly identify whether NCEs show dissolution rate limited or solubility rate limited absorption and thereby define the optimal formulation approach.1
Chris Cassidy - Vice President Sales & Marketing, SCHOTT North America: Self-administration of injectable drugs is a trend that continues to gain momentum. To facilitate patient safety and convenience of use, pharmaceutical companies are increasingly giving consideration to drug delivery pathways from the earliest stages of the drug development process. The expanded use of self-administered injectable drugs to treat chronic conditions such as diabetes and rheumatoid arthritis has led to growth in the market for ready-to-use devices. Drug manufacturers are also highly concerned with the quality and performance of primary packaging and components contained within delivery systems. The pharmaceutical industry invests a great deal of time and effort into the evaluation of packaging, components, and materials for parenteral drugs. By partnering with vendors during the early stages of the formulation process, pharmaceutical companies can ensure that they are selecting packaging and components that will perform appropriately in combination with drug products. This can help to avoid risk of interactions that could adulterate the drug product or impact efficacy. In addition, the risk of problems such as device failure, delamination, damage / breakage, and contamination can be eliminated to avoid market recalls.
Hibreniguss Terefe Ph.D., Vice President Research & Development, ExxPharma Therapeutics LLC: A search for new molecular entities (NME) using modern screening processes, such as combinatorial chemistry and drug design, is resulting with lead compounds that are increasingly lipophilic, poorly water soluble and having higher molecular weight. Approximately up to 90% of new drugs in the pipeline have bioavailability limitations, and, according to the Biopharmaceutical Classification System (BCS) fall into Class II (poorly soluble, highly permeable) and Class IV (poorly soluble, poorly permeable).
Patent expiration of brand drug products combined with shrinking R&D pipelines and high development cost necessitated implementation of life cycle management strategies that prolong patent life by improving the efficacy, safety and compliance of existing medicines. The generic market is highly competitive and obtaining approval through paragraph IV filing has become extremely difficult, especially for the smaller companies. Consequently, many generic companies often are shifting their focus towards specialty generics.
Therefore, drug delivery systems that improve efficacy, safety and patient compliance are in great demand and are highly sought after by pharmaceutical companies. Bioavailability enhancing drug delivery systems are instrumental in rendering poorly soluble new molecular entities viable medicines and in extending the life cycle of existing medicines that are approaching patent expiration. Pharmaceutical companies can utilize them to get products approved through the 505(b)(2) regulatory pathway. Modified release, abuse deterrent and fixed dose combination drug delivery systems also serve in making drug products more efficacious and safe. Moreover, they play an important role in improving patience compliance by reducing dose frequency and pill burden, and making dosage forms easy to administer. Demography tailored drug delivery systems, such geriatric and pediatric dosage forms, are also gaining importance.
Nick Grasman, Marketing Manager, Dow Food, Pharma & Medical: The number one issue that continues to drive research on drug delivery systems is the poor bioavailability of compounds emerging from discovery. Drug delivery issues are taking on increasing prominence in generic drugs as well. Recently there have been a few prominent examples of generic formulations which deviated from the delivery mechanism of the reference listed drug and were found to perform differently in-vivo, resulting in significant regulatory and market challenges. More than ever, formulators and drug developers need to engage with excipient suppliers to address these challenges.
Can you tell us about some new drug delivery technologies and/or processes that are helping pharmaceutical companies bring new products to market or are reviving older products? Is there a specific process or technology that you see as most effective?
Qiu: The enabling technologies AbbVie focuses on for low solubility/ bioavailability compounds include amorphous solid dispersions (ASDs) using Hot Melt Extrusion (HME) or spray drying manufacturing technology. Conventional approaches to enhance dissolution and oral absorption rely on increasing either solubility or surface area. ASD works on both; it allows dispersion of the amorphous drug at the molecular level in a stable polymeric system to increase apparent solubility while at the same time creating very small or even nanometer-sized particles to increase surface area during drug release. ASD formulation technologies, and associated manufacturing processes, can provide the maximized benefit of rapid dissolution of poorly soluble drugs. Both HME and spray drying technologies can be used to produce ASD and both involve a continuous operation that is amenable to continuous manufacturing. AbbVie has been working with HME for two decades. HME is preferred because it offers several advantages over spray drying: no solvents, smaller footprint, higher efficiency and lower operating cost. Depending on API and formulation, it also offers the opportunity of direct shaping, necessitating fewer processing steps. However, HME has its limitations depending on API properties. When it is not feasible for certain API’s due to thermal instability or limited drug loading, spray drying can be the alternative because it is applicable to a broader range of APIs and polymers without excessive heat exposure during manufacturing.
Kelemen: It is difficult to envision the development of novel drug delivery technologies without the realization that nanotechnology-based approaches are showing tremendous promise both experimentally and clinically. Perhaps this statement is most relevant in regards to the development of next generation immunotherapeutics and diagnostics. Relying on a widerange of technical capabilities and scientific disciplines, nanoparticlebased therapeutics offer very appealing approaches, for example, in tumor targeting either by passive or receptor-mediated active tumor targeting. These bioengineered nanoparticles can deliver immunotherapeutic agents that specifically kill cancer cells and, when combined with advanced drug delivery technologies, can direct therapeutics into regions of the body where classic formulations cannot effectively penetrate including across the blood-brain-barrier. The overarching benefits of nanoparticle-based drug delivery systems can be quite impactful on the therapeutic outcome for the patient. There is mounting evidence that nanoparticles can improve the therapeutics’ pharmacokinetics and pharmacodynamics profiles, reduce systemic or acute cellular toxicity and provide controlled and targeted release of the therapeutic agent.
Over the last several years there have been dedicated and significant advances in the development of nanotechnology-based vaccines for the invasive and non-invasive delivery of immunotherapeutic agents, especially nucleic acids. While several strategies have been developed over the years for RNA vaccine delivery, lipid nanoparticle formulations are being recognized as one of the more promising drug delivery systems for nucleic acids and show great promise towards achieving the goal of safe and efficient in vivo RNA delivery.
Matthew Shaffer, Manager, Multiparticulate Product Development, Lonza Pharma & Biotech: Multiparticulates (MPs) technologies are increasingly being selected as they are a proven life cycle management tool and highly flexible for achieving modified release delivery profiles, improved dosing regimens and fixed dose combinations. As an indication of their increasing value, 22 new drug products with multiparticulates were approved by the U.S. Food and Drug Administration between 2012 and 2016; 10 of the 22 approvals were for pediatric applications where multiparticulate formats are accepted as having superior dosing flexibility and ease of administration over monolithic formats.
Multiparticulates are frequently used for oral drug delivery when a compound is in need of microencapsulation, modified release, solubilization or combinations thereof. They are typically presented to the patient as capsules or sachets. The multi-unit particle approach presents advantages over other oral solids through reduced PK variability, flexibility in dosing and versatility in dosage form presentations.
The surge in utilizing multiparticulate technology is largely attributed to the development of pediatric products – as pediatric product development presents several unique challenges. Children are a vulnerable population at the peak of changes in both anatomy and physiology. From the youngest to oldest subpopulations, a broad range of doses and flexible dosing strategies are needed to accommodate these differences. Moreover, the dosage form presentation and product palatability are important to this population and their caregivers. Specialized MP technologies such as lipid multiparticulate technology provide inherent taste masking functionality through microencapsulation of the drug, and the flexibility to be delivered in multiple dosage forms. For example, in a sprinkle capsule presentation, the capsule could be swallowed, or the easy-to-swallow contents could be emptied directly in the mouth, or combined with food or liquids.
MPs have universal properties as well that can be adapted within a broad number of dosage forms for adults as well. The number of 505(b)2 approvals in recent years is evidence of this fact. Utilizing the lipid multiparticulate technology with a melt-spray congeal process, there is an opportunity to establish a platform-view on product development even for new compounds. Using this technology, a single development pathway for all ages going right into first-in-human trials is achievable. This approach could realize affordable medicines especially for niche indications, low margin markets, or even the geriatric population. Furthermore, it would enable speed to market by building product knowledge right out of the gate, thus minimizing the number of bridging studies during the product development.
As multiparticulates continue to demonstrate acceptability by patients, expect to see new, evolving presentations of the product and how it is administered – motivated by personalizing the delivery of medicine. Examples of personalization could include the development of reusable devices for dispensing that maintain the dosing flexibility, or offer patient choices to dosing aids that are more controlled than simply suggesting foods and beverages on the label. Lastly, with solubilized drug forms and high potency compounds becoming more common place in the industry, control strategies for multiparticulate technologies will need to adapt to see these compounds through to the market.
Stamoran: There’s fascinating work going on at both ends of the innovation range – well established formulation and dose platforms are being adapted to solve new challenges, and novel new predictive formulation optimization platforms are being developed to accelerate and optimize formulation development.
I’d highlight two examples from Catalent’s own work. First, in 2016, for the first time ever - in 200 years of soft gelatin capsule history – a sustained release softgel capsule received regulatory approval. Using a new shell system, OptiShell® technology, enabled a new fill modality, which becomes semi-solid after filling, in turn enabling a sustained rate of compound release for patients.
Secondly, I’d highlight that we have also created a predictive formulation platform of which I’m quite proud – the OptiForm® Solution Suite formulation platform. Starting with the idea that there’s no “one size fits all” approach to addressing solubility and bioavailability challenges, we combined a proven, solid-state chemistry high-throughput analysis platform with each of the key formulation enhancement approaches practiced today. Combining that with our own delivery expertise, built on over 80 years of formulation work, we’re able to quickly provide dose-form agnostic recommendations, saving customers the substantial amount of time and money it would take to do the same work experimentally, sequentially. We have now extended that into other areas, such as the complexities of oral peptide delivery, and most recently with complex release profile formulations.
Elder: Dissolution rate limited absorption can be addressed by API size reduction and the use of surfactants to facilitate rapid wetting. In contrast, solubility rate limited absorption can be addressed using amorphous stabilized formulations or alternatively using lipid formulations in softgel capsules to pre-solubilize the drug substance. The DCS1 approach allows companies to rapidly invest in the most suitable formulation strategy to optimize the potential for clinical success; thereby ensuring optimal development efficiency, whilst at the same time minimizing costs.
Cassidy: For drug products that must be lyophilized, double-chamber syringes offer a benefit to patients who self-administer the treatment. Freeze-dried medicines must be reconstituted with a diluent prior to injection. Double-chamber syringes allow patients to easily mix and administer medications through the use of a single, contained system. The drug product and diluent are prepacked in the double-chamber syringe, thereby avoiding the possibility of contamination and ensuring that the patient self-administers the proper dosage.
Terefe: Drug delivery is a broad topic but let us focus here on drug delivery technologies applicable to solid oral dosage forms and, more specifically, drug delivery technologies that enhance bioavailability. To enhance the bioavailability of poorly soluble drugs, basically two distinct strategies have been employed. The first strategy focuses at the API development stage and involves salt formation, prodrugs and search for more soluble analogs. The second strategy relies on drug delivery technologies that enhance the solubility of poorly soluble molecular entities, and hence drug absorption. Technologies that improve drug absorption in the gastro-intestinal tract include lipid-based formulations, micro-emulsions and self-emulsifying drug delivery systems, nano-particles and amorphous solid dispersions. Thanks to the extensive research and development activities that are being carried out by many companies to address bioavailability issues, the knowledge-base in this area is expanding and drug delivery systems increasingly becoming sophisticated. Drug delivery technologies have already led to the successful approval of several new molecular entities and product enhancements of approved drug products. Several amorphous solid dispersion-based drug products have been approved by the FDA and, the trend is going to continue as the technology gains more traction. While understanding the physicochemical properties of the target drug substance and selecting appropriate formulation components is the first step, it is also imperative that formulations are processed in the most effective way to obtain physically and chemically stable amorphous solid dispersions that provide maximum bioavailability. Hot melt extrusion has been proven to be a very efficient process to handle complex formulations when dealing with solubility enhancement. It is environment friendly and amenable to process analytical technology. The technology is versatile and could also be used to manufacture other types of drug delivery systems, such as modified release, fixed dose combination and abuse deterrent formulations.
Grasman: Brand new drug delivery technologies are rare, but we are seeing resurgence and growth in some niche technologies that are playing an important role. For example, extended release dosing via transdermal patches is an excellent means of improving compliance among populations that struggle to adhere to a strict dosing regimen. Likewise, multiparticulate dosing can help a formulator achieve multiple objectives by offering flexibility in drug release profile in a form which is much easier to swallow. Osmotic pump tablets have also demonstrated that they can be an effective way to mitigate variation in drug release as a result of fed/ fasted state. Finally, a number of innovative approaches are being explored to help address intentional abuse of analgesic medications.
How have functional excipients/raw materials helped with drug delivery? Are these excipients becoming more important as solubility concerns arise?
Qiu: Functional excipients are definitely becoming more important as solubility concerns arise; we cannot formulate drugs by ASD technologies without them. The challenge is to find the appropriate polymers, surfactants or other raw materials that will work for the molecular structure and physicochemical properties of the compound, to achieve increased dissolution and acceptable stability. You need a certain type of polymer and its functional properties to enable formulation and function of ASD.
Elder: The DCS1 formulation strategies, particularly those applied for solubility-limited NCEs can only be implemented using functional excipients. In the case of softgel development these excipient facilitate solubility in a lipidic vehicle that can rapidly form an emulsion (typically micro- or nanosized) on contact with the gastro-intestinal environment. For amorphous stabilized formulation approaches the functional excipients minimize molecular mobility by trapping the amorphous API in an extended H-bonded network. The amorphous API has intrinsically higher aqueous solubility than its crystalline counter-part, but suffer from reduced chemical and/or physical stability. Such approaches can produce products with realistic, commercially aligned shelf-lives, i.e. 24+ months by reducing chemical instability as well as enhancing physical stability by retarding/preventing conversion of the amorphous API into the thermodynamically more stable crystalline entity.
Cassidy: The rise of self-medication has led to the expectation that parenteral devices should be easy to use. Silicone has been the primary lubricant used in pre-filled syringes to reduce glide force and preserve patient comfort. However, the use of lubricants can result in the presence of visual particulates and may cause interactions with drug products. Particulates and potential drug interactions are major areas of concern that drug manufacturers consider when selecting drug delivery devices, components, and packaging materials. Pharmaceutical companies must partner with suppliers who effectively manage these risks throughout every step of the manufacturing process. Primary packaging and components should be produced from materials of the highest purity to reduce the risk of extractables and leachables, and to prevent heavy metal contamination or ion release. Cross-linked silicone reduces subvisible particulates. Certain sterilization methods have significant advantages over others when it comes to the reduction of extractables and leachables. Material concerns play a major role in medication safety.
Terefe: Functional excipients are critical components of drug delivery systems. Because of strict regulatory requirements, the list of available excipients that could be used for solubility enhancement is very limited. Recognizing this need, excipient manufacturers are coming up with improved and innovative solutions to address solubility issues. To mention some, BASF’s Soluplus® is a new functional excipient that was developed to enhance solubility of poorly soluble drug substances during hot melt extrusion. Dow chemicals has introduced Affinisol® systems, i.e. HPMC and HPMCAS grades that have improved thermal properties for successful HME processing. Evonik is expanding the application of Eudragit® polymers for hot melt extrusion applications. Gattefosse is offering a range of pharmaceutical excipients that could be used in the development of lipid based and selfemulsifying drug delivery systems.
Grasman: Without a doubt, active ingredients are becoming more targeted and more demanding placing increasing pressure on excipients to step up to the challenge. Across the board, excipient providers have been elevating their performance by improving batch to batch consistency and innovating within compendial limits, but the challenges of the future will likely require novel excipients. Creation of a pathway for novel excipients that allows for excipients to demonstrate their safety and receive approval independently from a drug application remains a key barrier to breakthrough development.
As drug delivery issues become more commonplace – what is the role of suppliers to industry? How important is their product/formulation experience to the success of any given product?
Qiu: The experience of a supplier or service provider is, of course, critical to the success of drug delivery. For a CDMO, such as AbbVie, you need to be able to demonstrate your skills and experiences in delivering a drug product to market. Can you develop a formulation and handle the technology transfer or scale it up for commercial manufacture? What happens when you run into inevitable hiccups? Does the CDMO have processes in place and a culture of transparency, communication, and ownership to convey the problem and possible solutions? And the ability to work with the client toward an agreed solution? In every respect, experience and knowledge are highly valuable to pharmaceutical sponsors who already have invested significantly in their compounds.
Kelemen: As a cGMP manufacturer and supplier of functional lipid excipients for drug formulation and delivery applications, our level of commitment towards providing the highest quality monographed excipients to the pharmaceutical industry cannot be overstated. In support of a diverse catalog of functional lipid products, we strongly believe that it is imperative to have first-hand knowledge and application experience in the use of our excipients. This knowledge base expands across a wide range of formulation types and delivery challenges including the development of self-emulsifying drug delivery systems for BCS Class II-IV small molecules into the development of complex lipid nanoparticle formulations for the non-invasive delivery of biologic drugs. The author believes that it is the obligation and responsibility of excipient suppliers to maintain a highdegree of scientific knowledge in order to support the pharmaceutical industry in their quest for the successful development of safe and effective next generation therapeutics.
Stamoran: There are a few different business models that suppliers of drug delivery services and technologies follow. Some purely supply an excipient or component – a specific device, for example. Others can provide early-stage formulation design, but lack capabilities to produce it at clinical or commercial scale. And then some providers – like Catalent – believe it’s important that you formulate not just for outcomes but also for manufacturability, and that it’s critical to be able to take your customer’s product from the first preclinical dose all the way through the millionth – or billionth – dose on the market. And then follow through by making the investments to bring the “best in class” providers of those capabilities in house.
There’s substantial published research that suggests linkages between drug substance and drug product design decisions and key drivers of patient outcomes, such as patient adherence, side effect profiles, and discontinuation. Through the Catalent Applied Drug Delivery Institute, we’re trying to formalize and extend this research, including via a research collaboration on drug delivery for young pediatric patients that we’ve recently signed with the Rutgers University School of Pharmacy, and ongoing work in oncology drug delivery too.
Elder: The key attributes that suppliers can provide is knowledge and expertise. Poor solubility is an issue that they are very familiar with and they will have extensive experience on the best strategies to address this problem.
Cassidy: Suppliers have become partners and consultants to the pharmaceutical industry. It is vitally important that vendors of primary packaging, components, and drug delivery systems are engaged by pharmaceutical manufacturers during the early stages of drug development. Very often, several vendors must work together for the benefit of their mutual pharma customer. Drug makers are increasingly asking packaging suppliers for testing related to toxicity and leachables in a product. Also, drug products that have moderate to severe delamination risks must undergo additional compliance testing for shelf life and stability. The pharmaceutical industry has particularly complex supply chains, and packaging is just one of the many variables they must control. Pharmaceutical companies operating drug development processes that allow for integrated collaboration with suppliers reap significant benefits, and are more likely to avoid pitfalls in the late-stage clinical and post-launch phases.
Terefe: The pharmaceutical industry is highly competitive, and riskaverse. Companies want to win the race by having the best possible quality product, in the shortest possible time, with the minimum possible expense and risk. For that to happen, a number of factors must be satisfied. For successful product development, the supplier should have not only knowledge and experience in solving drug delivery issues, but also good understanding about the regulatory requirement throughout the product development phases. As every drug substance is unique, the development process should be guided by good science. Cost-effective, phase-appropriate development plan that shortens development time is crucial, especially for small discovery companies that operate in funding constrained environment. Such demanding service requires extensive product and formulation development experience.
Grasman: Suppliers represent a significant source of underutilized information to formulators and product developers. In my experience, when formulators and excipient providers have truly and openly engaged with one another, significant challenges have been surmounted. All too often, suppliers and developers have a relationship that extends only to exchanging small bits of information which does not allow for the kind of collaborative problem solving that today’s drug delivery challenges require.
If a company is having drug delivery/solubility problems with a product in development is there a “checklist” of items/steps, based on the latest technologies that they need to review before shelving a product?
Qiu: AbbVie goes through a comprehensive review before considering shelving a product. Essentially, we will re-examine everything that went into development of the molecule, its formulation, and manufacturing to see if anything can be modified or changed to improve the outcome. Of course we try to course-adjust along the way, considering every angle as we go to achieve the best outcome. But if we find a problem we didn’t anticipate and need to go back, we do a rigorous review and bring in subject-matter experts as well as new people, a fresh set of eyes to examine the problem. You can see what we have in place is better than a simple check list.
Stamoran: What I’ve often seen happen – a company’s R&D team will have one or more people familiar with at least one formulation enhancement platform, say particle-size reduction. They try to explore that approach with an early target candidate, and then if it’s insufficient, they may choose to move on to other target variants, or to sequentially try a second formulation approach. This consumes both time and money, both of which are in short supply!
I have yet to see a checklist or off-the-shelf tool to do this – the intersection between chemistry and biology is complex, and patients are diverse. I believe using a platform such as the OptiForm® Solution Suite formulation platform, and partnering with an experienced early development provider (like Catalent), will deliver the best results. And the earlier in the development path, the better.
Elder: The DCS1 approach is useful because in addition to providing a framework for relevant formulation strategies designed to address poor aqueous solubility, this approach can identify the likelihood of success. Based on relevant, cross-industry experience we know that DCS class 4 compounds (i.e. poor solubility and permeability) have significantly increased likelihood of attrition and that it will take much longer to demonstrate this during clinical development. 2 Fridgeirsdottir et al.3 used guidance maps and formulation decision trees to facilitate in the rapid identification of an appropriate -enabling formulation technology.
Cassidy: Solutions always exist. To find these solutions, drug manufacturers must work closely with their suppliers to examine the entire filling process to evaluate the intended use of each component utilized. A holistic approach is required. From the early stages of drug formulation, the drug manufacturers must identify materials that meet the particular requirements of the product in question. Careful consideration must be given to the many potential risks that exist. Does the drug require particularly inert packaging? Is there any flexibility on device design? Is there a need for tight tolerances? Do any of the components require superior break-force resistance? Packaging and component material candidates must be evaluated for compatibility with existing filling lines. Patient safety and comfort must always remain in focus as top priorities. Each material utilized with have strengths and weaknesses. It is up to the drug manufacturers to obtain all of the relevant information to make informed choices regarding components, packaging, and delivery devices.
Terefe: Understanding physicochemical and biopharmaceutical properties of a drug substance is the first step to successful drug product development. Having exhaustive pre-formulation studies and determining BCS classifications help to plan and prioritize which technologies and formulations to consider. For example, is the poor solubility crystal lattice energy-limited or solvation-limited? For predominantly hydrophobic drugs that are solvation limited, lipid-based formulations and selfemulsifying drug delivery systems may be a place to start. For crystal lattice energy-limited poorly-soluble drugs, amorphous solid dispersion may be the way to go. Relevant questions include: Does the drug exhibit high melting point and high hydrophobicity? What is the propensity of the drug to recrystallize once converted into amorphous form? Computational methods that use molecular modeling and solubility parameters are helpful to select appropriate carrier polymers for the development of amorphous solid dispersions. Depending on the physicochemical properties of the drug substances, the most appropriate technologies with appropriate formulations shall be rationally selected.
Grasman: In today’s world, there are a wide variety of options available for tackling a particular drug delivery challenge. Knowing where to start and when to call it quits are key skills that anyone developing new formulations must acquire. There is a very real desire to try and create a sort of flow-sheet that can be used to help guide formulation development, but this idea is based on the premise that one particular technology is more likely to work than another in nearly every situation. More often, I find the challenge for drug development is efficiently expanding options beyond the typical checklist. CROs and suppliers can be excellent sources of information for expanding the suite of options to make sure that a valuable discovery is not discarded due to delivery mismatch.
What do you see as the major industry critical issues over the next five years in regards to drug delivery?
Qiu: For solid oral products, and the APIs involved, we expect the trend of poor solubility to continue. The compounds will only get more challenging to formulate, but we’re confident we’ll meet those challenges. In the area of formulation technology, we’ll still be challenged with drug loading. Right now the percentage of drug in a formulation is relatively low – often less than 30% and more often about 10 - 20%. That can result in the need for multiple pills or single large pills that patients must swallow to get the therapeutic dose. This is an area where we are constantly striving to improve through product and process research. Finally, in the manufacturing process, product and manufacturing consistency is an issue regulators are paying increased attention to. Continuous manufacturing may be one of the solutions here, and HME, which AbbVie uses, is amenable to continuous manufacturing.
Stamoran: Delivering to the target activity site while minimizing impact on other non-targeted areas will be increasingly important for biologics and other drugs, as will determining how best to deliver new modalities like gene and cell therapy.
Finding ways to address the “adherence problem”: I believe designing drug products to improve patient outcomes will play a significant role, as will identifying ways to deal with polypharmacy issue, including regimens that are predominantly generic.
Finally, product developers must be prepared to demonstrate proof of incremental value versus currently available treatments, and if they’re using an enhancing drug delivery technology, proof that such actually has an incremental impact; to justify formulary placement, market access or cost.
Cassidy: In order to develop more effective cures and treatments, the pharmaceutical industry is fundamentally shifting from large batch, “onesize-fits-all” drugs to targeted medications, therapeutic niche applications, and high-value biologic drugs. These highly specialized therapies focus on smaller patient populations, and thus are produced in smaller volumes. In the past, pharmaceutical manufacturers have tended to build filling lines that are geared toward high-quantity production batches. However, in the future, drug manufactures will need to fill small-quantity batches and will utilize different types of containers on the same filling line. The pharma production process will require the ability to make quick job changes and setups. Not only will a drug product change from batch-to-batch, but the type of container being filled may change as well. During the course of a week, the same filling line may be utilized to fill vials, syringes, and cartridges. Next generation filling lines will require such flexibility in order to reduce time-to-market and avoid the risk of drug shortages. One of the best ways for pharmaceutical manufacturers to achieve flexibility in an era of smaller batch sizes is to rely on the traditional nest and tub configurations for ready-to-use containers, components and devices. These configurations work on a variety of machine types, and allow pharmaceutical manufacturers to quickly and easily shift from vials to cartridges to pre-filled syringes all on the same line. By standardizing drug manufacturing and filling, the time required for regulatory review of new processes, materials, and components can be reduced.
Terefe: Biopharmaceutical companies are discovering more and more complex small and large molecules which pose difficult drug delivery and manufacturing issues. The need for the development of drug delivery systems that accurately deliver drugs to targeted body sites must be addressed more than before. Another issue that is challenging is the development of age-appropriate pediatric and geriatric patients-focused versatile drug delivery systems.
Pediatric patients differ in their developmental status and dosing requirements from adults. Geriatric patients have compromised pharmacokinetics affected by co-morbidity, reduced organ function and multiple drug use. Hence most conventional drug delivery systems are not acceptable for these demographic groups.
Grasman: With Biologics being the largest growth segment for the Pharmaceutical Industry, the biggest challenge will be patient’s compliance with the delivery of the API. Oral delivery is the largest delivery solution today and Biologics typical route is parental because of the API’s interaction with the gastrointestinal tract. I expect more innovation in the combination medical devices like the wearable insulin pump patch to improve the parental delivery experience.
References
- J.M. Butler, J. Dressman. 2010. The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development. J. Pharm. Sci., 99(12), 4940-4954.
- M.K. Bayliss, J.M. Butler, P.L. Feldman PL, et al. 2016. Quality guidelines for oral drug candidates:
- dose, solubility and lipophilicity. Drug Discov. Today.;21(10), 1719-1727.
- G.A. Fridgeirsdottir, R. Harris, P.M. Fischer, C.J. Roberts CJ. 2016. Support tools in formulation development for poorly soluble drugs. J Pharm. Sci. 105(8), 2260-2269.