The following charts the twin rise of biologics and PFS and outlines some of the common challenges associated with filling and dispensing. It also discusses how a patient-centric partnership approach, based on a culture of collaboration and communication, can help biopharmaceutical companies shorten the development pathway and ensure a reliable supply of safe, effective medicines for the people who need them. BIOLOGICS: THE MEDICINES OF THE FUTURE Recent years have seen some of the biggest leaps in medical science in history. Researchers, driven by rapidly evolving technology and an ever-greater understanding of the underlying mechanisms of disease, have developed a growing number of products that have proved to be nothing short of life-changing. Much of this progress can be attributed to the rise of biologics, or drug products derived from the components of living organisms. Molecular biologists have been able to isolate and purify naturally occurring proteins, such as hormones and antibodies, and then administer them to those whose bodies lack them. The first genetically engineered form of insulin, which replicated the form of the protein found in the human body, was approved in 1982.1 By the mid-1990s, scientists had improved upon this early insulin by altering the protein’s amino acid sequence and changing its properties.1 The first genetically engineered form of insulin, which replicated the form of the protein found in the human body, was approved in 1982.1 By the mid-1990s, scientists had improved upon this early insulin by altering the protein’s amino acid sequence and changing its properties.1 Around this same time, the first antibodies were approved for use in humans, opening the door to the possibility of new drug products that could block the function of specific proteins. Since then, progress has been swift and, today, antibody-based drug products are common in the treatment of several long-term conditions. The previously untreatable progressive neurological condition multiple sclerosis (MS) is one such example. While scientists have yet to find a cure for the condition, disease-modifying drugs, many of which are biologics, are routinely used to slow the progression of the disease and reduce relapse rates, allowing patients to remain active longer than originally anticipated.2 We are now set for the next giant leap, as the tremendous promise of next-generation gene and cell therapies begin to bear fruit. Clinical trials have suggested that cell therapies could play a revolutionary role in cancer treatments, and that gene editing could even reverse blindness caused by specific genetic mutations. In 2018, the FDA had 500 active investigational new drug applications involving gene therapy products, and $2.3 billion in funding has been pumped into private gene therapy companies throughout the past 10 years.3 As many “first-wave” biological products reach the end of their patent period, biosimilars are becoming increasingly common – approximately 50 have been launched since 2010, and many more are in the pipeline.4 Their development highlights their complexity. Biosimilars, or follow-on biologics, are not generics. Every batch of a biologic medicine, whether it is a vaccine, blood component, allergenic, somatic cell, gene therapy, or recombinant therapeutic protein, is biologically different to the one that came before. Simply recreating it, as would be seen in traditional, large molecule drug production, is not an option. In the US and European Union, manufacturers must demonstrate that there are no clinically meaningful differences in terms of quality, safety, and effectiveness between their product and the reference product.5 This involves a robust testing process. The success of biological products overall is demonstrated in the data. Since the first genetically engineered insulin was marketed in 1982, almost 300 biologic drugs have been developed, patented and approved.4 In 2018, the biopharmaceutical industry was worth $210 billion, and an estimated 60% to 70% of drugs currently in development are biological products.4,6 All this makes for a fiercely competitive marketplace, but the drugs themselves are not the sole marker of success. Far from being an afterthought, delivery systems are an integral component of the biological drug development pathway. PFS: THE DELIVERY SYSTEM OF THE FUTURE While it is fair to say that biologics have driven, and continue to drive personalized care, administering these medicines presents a challenge. They are complex products that require complex delivery systems. Tablets, capsules, and pills, the mainstay of traditional, small molecule medicine, are not suitable for biological medications due to high levels of degradation in the gut. This class of medicine must be delivered parenterally, usually intravenously, subcutaneously, or intramuscularly. When compared with needle and vial systems, PFS has emerged as the preferred delivery method for biologics for a variety of reasons. Delivery via PFS is better suited to emergency situations and remote areas and is ideal for the self-administration required for the delivery of many monoclonal antibodies used in, for example, long-term conditions. They also can reduce dosing errors by facilitating the provision of exact doses. In addition to the obvious compliance and safety benefits, this also plays into cost considerations. Multi- and single-dose vials typically have a drug overfill of between 20% and 25% to account for human error — a significant cost implication when manufacturing large quantities of expensive proteins and peptides.7 What’s more, the high viscosity of biological products, and therefore the pressure needed to inject them, makes the use of traditional vial-based syringes extremely challenging. This is particularly pertinent when the medication is being used at home by someone with a condition that can affect dexterity, such as MS. As the number and range of biological treatments have grown, so has the utilization of PFS as an effective delivery system. As of 2017, nine of the top 10 PFS-delivered drug products were biologics, a trend that is expected to increase as next-generation gene and cell therapies come online.8 CHALLENGES: PREFILLED, NOT EASILY FILLED The synergy in the rise of biological medicines and PFS is clear, but the relationship between product and delivery system isn’t without its challenges. Simply put, prefilled does not mean easily filled. Each complex protein or peptide medication is unique in its formulation, use, and safety profile, necessitating bespoke manufacturing, sterilization, filling, and compliance procedures. To build such processes, PFS manufacturers need to consider all factors, including efficacy, active pharmaceutical ingredients (APIs), the product’s characteristics and safety profile, and the preferences of the end-user. Ironically, one of the most widely discussed challenges in formulating and filling PFS with biologics centers around one of the primary reasons they are so compatible – product viscosity. The high-dose requirements of many monoclonal antibodies (MAbs), for instance, mean they must be formulated at high concentrations, increasing their viscosity. A major challenge with filling such a highly viscous product is being able to cleanly dispense the product into the syringes. The solution will often stick to the tip of the filling needle, creating a trail of product along the syringe as the needle withdraws after dispensing. A common method to overcome this problem is reducing viscosity through heat. However, this is not valid for many biologics, including MAbs of which solution stability is temperature dependent. Other approaches have looked at fill needle movement. Some use a short, quick downward motion before needle retraction to break surface tension. However, this approach is problematic when filling products over 1,000 centipoise into polymer syringes. AMRI’s own solution involves using a high-speed camera to film the needle motion, then aligning the retracting motion of the needles to the velocity of the pump motion dispensing of product. This process, which implements a short pause above the final liquid level, ensures the remaining product disconnects from the needle tip. It’s an effective method, but it must be adapted to suit each medicine we work with. Another PFS consideration is the choice between glass or plastic syringes, which are typically made from either cyclo olefin polymer (COP) and cyclo olefin copolymer (COC). Plastic has become increasingly common in recent years – not least in biologics of which viscosity means products need to be stored in packaging that allows for a consistent gliding force during administration. However, it is not always the right solution for the product. Several factors need to be considered, and drug and PFS manufacturers will often work together to holistically assess the three Ps: Product, Process, and Patient. The importance of design flexibility, tighter tolerance, and break resistance, whether the PFS will be integrated with a safety device or autoinjector, and patient comfort will all be considered. Where polymer is the preferred route, filling can be difficult. Improperly programmed machine movements or even minor equipment defects can cause scratches and increase the unit rejection rate. Much of the industry attempts to overcome this with vacuum stoppering, though it is important to note that this solution doesn’t work with all products or container closure systems. Instead, AMRI has developed expertise to assess each case across a variety of syringe sizes and implement custom solutions. AMRI has also developed custom tools that verify all critical components are mechanically aligned before each filling campaign, which minimizes scratching. Extractables and leachables (E&Ls), which can interfere with the drug molecules and compromise the product’s effectiveness, present another challenge to the pairing of biological medications and PFS. Whereas products in vials only come into contact with glass and rubber, those provided in PFS are exposed to most of the delivery system’s materials and components, multiplying the likelihood of interactions. Hence, the PFS market is heavily regulated, with the FDA and EMA, representing the world’s two biggest markets for biologics, setting strict guidelines on the filling and dispensing of PFS to enforce risk reduction. It is another example of how there is no off-the-shelf solution to PFS. The selection of materials and components involves a detailed assessment of biocompatibility, formulations and risk profiles, as well as an encyclopaedic knowledge of the relevant compliance processes. AMRI’s in-house analytical team’s expertise in extractables and leachables, container testing, and heavy metal detection significantly aids in optimizing container closure design for any given product, and is a valuable resource for our clients. THE VALUE OF PARTNERSHIP IN A PATIENT-DRIVEN WORLD Overcoming the multitude of manufacturing and process challenges associated with biologics and PFS – and fulfilling the potential of this product/delivery system coupling – requires partnership. The biological medicines marketplace is fiercely competitive, and with the average drug development pathway taking 10 years and costing $2.6 billion, there is little room for error.9 Quite simply, there is no point to developing an innovative, life-changing drug if people cannot use it. Combining pharmaceutical and drug delivery expertise as early on in the development process as possible can help speed up the pathway, while ensuring new medicines are safe, effective, easy to use, and tackle unmet patient needs. There is no one-size-fits-all solution. Every product is unique, requiring custom mechanical, technical, and compliance processes. Industry-leading CDMOs can take a more agile approach that adapts to the needs of each product and its end users. Every patient group will have differing requirements of both the product itself and the packaging it is supplied in. Therefore, the PFS design and development must evolve in parallel to product design and development. Indeed, many drug developers work with their chosen PFS supplier as early as Phase 1 to ensure the end result meets the needs of the product and patient. The formulation of some solutions, for example, requires the addition of several kilograms of excipients in a low oxygen environment. The whole process, including weighing and transfer, must be conducted within an active nitrogen overlay with low oxygen permeability. Rather than spend a huge amount on a complicated, automated system that would result in significant residual powder losses, AMRI worked with Solo Containment Ltd and Servolift LLC to engineer a custom solution for our clients. The resulting system features an isolator unit with docking station for split butterfly valves and powder containment bags. It allows for large amounts of powder to be moved from isolator to tank in a low-oxygen environment, facilitating the precise addition of the powders to the formulation vessel, and minimizing product loss. SUMMARY The rise of biologic medicines plays a major role in the growth of the PFS market. These cutting-edge treatments have necessitated a shift from oral to parenteral administration, creating a need for state-of-the-art, innovative delivery systems, and the trend is set to continue as more biosimilars, and next-generation gene and cell therapies, come online. However, dispensing highly viscous solutions, minimizing E&Ls, and ensuring biocompatibility, all while developing delivery systems that suit individual patient groups, presents unique manufacturing, compliance, filling, and dispensing challenges. CDMOs with integrated expertise streamline product development and optimization. Close working relationships, both within the organization and with partners and clients, speed up problem-solving and facilitate the creation of bespoke solutions. By partnering with PFS CDMOs, biopharmaceutical companies can benefit from specialized expertise and expect shorter, smoother development pathways. These strong partnerships, working together to develop custom solutions, are the best way to ensure that innovative biologic treatments are delivered effectively, fulfil their potential and, ultimately, save lives. REFERENCES Rise of the biologics by Derek Lowe. Published by MedChemComm, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071940/. Drug therapy for multiple sclerosis by Eleonora Tavazzi et al. Published by CMAJ JAMC, 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119143/. Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine by Kris Elverum and Maria Whitman. Published by Nature, 2019. https://www.nature.com/articles/s41434-019-0074-7. Current perspectives on biosimilars by Frank Agbogbo et al. Published by Fermentation, Cell Culture and Bioengineering Review, 2019. https://link.springer.com/article/10.1007/s10295-019-02216-z. Regulatory explainer: Everything you need to know about biosimilars by Zachary Brennon. Published by Regulatory Focus, 2018. Regulatory Explainer: Everything You Need to Know About Biosimilars. The new administration – prefilled syringes and auto-injectors by NS Healthcare Staff Writer. Published by NS Healthcare, 2014. https://www.nshealthcare.com/analysis/the-new-administration-prefilled-…. Pre-filled syringes: Getting to the point by Chris Lo. Published by Pharmaceutical Technology, 2011. https://www.pharmaceutical-technology.com/features/featureprefilled-syr…. Impact of PFS and filling process selection on biologic product stability by Wendy Saffell-Clemmer. Published by BioPharm International, 2017. http://www.biopharminternational.com/impact-pfs-and-filling-process-sel…. Biopharmaceutical research and development by PhRMA. Published by PhRMA, 2015. http://phrmadocs.phrma.org/sites/default/files/pdf/rd_brochure_022307.p…. To view this issue and all back issues online, please visit www.drug-dev.com. Anish Parikh, AMRI’s Vice President, Drug Product Sales & Marketing, has more than 25 years of R&D, sales, and marketing experience in the pharmaceutical industry. He earned his Bachelor’s degrees in Molecular Biology and Biochemistry (MBB) as well as Psychology from Rutgers College at Rutgers University in New Brunswick, NJ.
