3

Innovations in Manufacturing Drug Products

As noted in Chapter 2, production of the nation’s drug supply involves manufacture of the drug substances—the active pharmaceutical ingredients (APIs)—and ultimately of the drug products that are delivered to patients. In this chapter, the committee focuses on the manufacture of drug products. The discussion is organized into three major sections. The first describes innovations in the manufacture of conventional drug products, the second highlights innovations in drug-product forms, and the third focuses on novel excipients that enable new drug-product formulations. In addition to highlighting the emerging technologies, the committee describes technical and regulatory challenges associated with the drug-product technologies and provides recommendations for overcoming the regulatory challenges.

INNOVATIONS IN MANUFACTURING APPROACHES FOR CONVENTIONAL DRUG PRODUCTS

The concept of continuous improvement is a philosophy of most pharmaceutical manufacturers as they strive to increase supply, gain efficiencies, and decrease costs. Innovations in the unit operations that make up the last few steps in the processing of conventional drug products are often the key to making such improvements. Such innovations are classified into three categories—additive manufacturing, lyophilization, and aseptic processing—and are described in the following sections.

Additive Manufacturing

Additive manufacturing (AM), or product formation by using 3-dimensional (3-D) printing, has been an innovation that has swept through the manufacturing sector. Indeed, one of the national manufacturing institutes launched under the Obama administration, America Makes, focuses on AM and has drawn much attention to and useful application of this technology. One of the challenges or opportunities of AM is that it takes many forms, which can be classified in various ways. For example, ASTM International has proposed categorizing AM into vat photopolymerization, material jetting, binder jetting, material extrusion, powder-bed fusion, sheet lamination, and directed energy deposition (ASTM 2012). Although there have been numerous explorations of the use of virtually all those forms for pharmaceutical-dose production at the research and development stage, only a few are sufficiently advanced to be commercially viable within 5–10 years (Jamroz et al. 2018). The three broad categories of AM forms that are most promising are powder solidification, liquid solidification, and extrusion-based systems.

The powder solidification route has been used to produce one approved product (NASEM 2020). In that system, a binder fluid is jetted onto a thin bed of powder blend, which includes the API, in a specific pattern that forms the tablet cross-section. That action causes the affected particles to bind, the powder left unbound is removed, and the process is repeated with multiple successive layers of powder blend until the tablet of desired size is attained. The tablet is then dried to remove the binder fluid. Further advances in this process have been announced; the powder blend is now deposited in successive thin layers in a well or blister, thus reducing the reprocessing of unbound powder but increasing the demands on good powder flow.

The liquid solidification route is exemplified by a technology in which a solution that contains the API is printed onto an excipient tablet and the solution dried to create the dosage form (Clarke et al. 2017). The manufacturing technology has been implemented at scale, but no product that uses it has yet been approved. Research success in the use of alternative fluid formulations—including polymer melts and suspensions of API powders (Içten et al. 2017; Radcliffe et al. 2019)—have been reported. In all cases, a solid is produced by drying to remove the solvent or by cooling to solidify the fluid formulation and thus form a stable dosage form. However, no products that use the liquid solidification route have been approved.

Extrusion-based methods, specifically those using drug-polymer filaments (Awad et al 2018), are among the most frequently reported AM methods. They can take advantage of a wide array of commercially available 3-D printing devices that can process thermoplastic polymeric filaments. To produce a dosage form, a filament that consists of a suitable polymer—a drug mixture that has the desired API composition and appropriate mechanical or rheologic properties—must be prepared. That approach requires some form of hot-melt extrusion as a preparatory step.

The common advantages of AM forms are that they are inherently continuous, allow virtually 100% monitoring of dosage forms produced, and allow rejection of faulty product at the level of an individual dose rather than a batch. Furthermore, production equipment can be scaled down to a compact size (close to bench-top size), thus enabling distributed manufacturing. With simple adjustment of the number of powder layers, the number of drops, or the amount of filament deposited, AM forms lend themselves to tailoring the dosage to the patient. AM also readily accommodates alternative 3-D shapes and thus tablet designs. The additive mode also allows introduction of multiple feed materials and thus facilitates the production of combination products and various controlled-release dosage designs.

Technical Challenges

Common technical challenges are achieving production rates that are competitive with traditional tableting or capsule-filling lines and instituting process control that is based on process analytic technology (PAT) of critical product attributes. Process control is typically restricted to control of the material deposition step rather than of critical product attributes. Another important challenge is the physics-based modeling to support development of operating regimens for classes of AM methods or design spaces for specific AM applications. Predictive modeling has advanced; for example, there are finite-element computational fluid mechanics models of drop formation (Basaran et al. 2013) and multi-physics models of extrusion deposition (Brenken et al. 2019). However, aspects that still need to be addressed include treatment of more complex formulations, such as suspensions; capture of effects of non-Newtonian fluid properties; and prediction of drop penetration into powder beds that are composed of heterogeneous blends. Beyond those common challenges, each AM form is subject to its own characteristic technical challenges, some of which are listed below.

• Powder solidification. Challenges include limitations of mechanical properties, such as porosity of the tablets produced; ensuring blend uniformity; recycling of powder blend that is left unbound; interaction between properties of the binder fluid and of the powder blend; and flowability of the powder blend.
• Liquid solidification. Challenges include the effect of a liquid’s flow characteristics on the complexity and reproducibility of the drop formation process and control of the API crystal form during the solidification process.
• Extrusion-based methods. Challenges include production of filaments that have suitable mechanical properties, exposure of the API to two heating steps, control of the API crystal form during solidification process, and the limited number of polymer excipients that have been approved for human consumption.

Regulatory Challenges

A common regulatory challenge arises in the approval process for the technology: an integrated AM system is not approved as a technology independent of site but at each individual implementation site. In the application of AM to produce dosages that are individualized to meet the needs of specific patients, the question arises of whether the production should be treated as manufacturing or as compounding. Given the commonality of the AM methods in their exploitation of fluid-processing steps to form individual doses, it would be desirable to have comprehensive guidelines that cover the entire family of AM methods despite the variability in implementation details. Given the direct links among 3-D representation, printing execution, and processing conditions, the guidelines should cover software and hardware requirements, drug-substance stability considerations during and after processing, and product-quality monitoring and control. The guidance on additive manufactured medical devices (FDA 2018) could serve as a starting point for AM guidance.

Lyophilization

Although AM innovations focus largely on solid oral dosage products of small-molecule APIs, the vast majority of large-molecule–based therapies are administered through injection or infusion. In recent years, nearly half the newly approved injectable or infusible products have required lyophilization to ensure product stability (Alexeenko and Topp 2020). As currently practiced, lyophilization is a highly inefficient batch process in which

solvent is removed from a liquid formulation via sublimation of solvent, normally water, at low temperature and pressure. Given the limited global lyophilization capacity and the increasing number of products that require lyophilization, there is a substantial incentive to create and deploy new technology. In late 2017, the LyoHUB consortium issued a technology roadmap that addresses gaps in product design methods, process technology, and process equipment.¹ The manufacturing innovations that have been introduced in recent years to address those gaps consist of improvements in traditional batch-mode operations, continuous lyophilization that uses serial processing of vials, and continuous bulk lyophilization.

The most immediately implementable innovations of lyophilization are improvements in open-loop batch operations and include the development of sensors and PAT methods for monitoring product attributes, development of predictive first-principles models of heat- and mass-transfer processes, and implementation of model-based process control. Among PAT methods of particular importance for product quality are nondestructive measurements of residual moisture content that use spectroscopic methods that can be implemented on multiple scales. Important operational strategy modifications are approaches to controlled (primary) ice nucleation. Currently, primary nucleation takes place in uncontrolled fashion as a natural stochastic process that results in longer processing times and poor porosity of the dried product. Rapid depressurization is one approach for achieving such nucleation that appears to be most readily implemented. Although the improvements do not change the batch character of the lyophilization operation, they nonetheless require substantial modifications of equipment and changes in manufacturing culture and workforce skills.

Continuous lyophilization methods include conversion from the traditional tray-style batch lyophilizer designs to continuous systems in which vials are processed sequentially through nucleation and drying stages and that include enhancements, such as spinning of vials, to increase surface area for heat and mass transfer (De Meyer et al. 2015; Capozi et al. 2019). Additional improvements include acceleration of the freeze-drying process by using electromagnetic radiation from infrared heaters or by using radiofrequency dielectric heating.

Another innovation in this field is freeze drying in bulk by using such technologies as spray freeze-drying. The spray process provides a larger surface area for sublimation and allows faster heat transfer by forced convection or radiant heating. An alternative route involves the use of multiple successive mechanically agitated stirred vessels, each operating a specific freeze-drying phase (Touzet et al. 2018) Continuous operation enables complete containment and can produce aseptic dried particles that can then be filled into vials under aseptic conditions once the desired residual moisture content and particle-size distribution are achieved.

Application of microwave energy under vacuum conditions can also achieve rapid dehydration of a frozen product. In this process, energy transfer occurs by microwave radiation into the entire frozen mass rather than just by heat transfer from the bottom of the vial. To achieve uniform heat transfer, a configuration with multiple magnetrons is used. Microwave drying allows freeze-drying cycle times to be reduced from several days to several hours. This technology offers the considerable advantages of lower energy, capital cost, and intra-batch variability compared with conventional lyophilization. Moreover, the smaller footprint and lower cost of this drying mode could allow scale up from development to manufacturing simply by addition of parallel units.

Technical Challenges

The technical challenges of improving batch operations lie first in process instrumentation, especially the lack of robust and affordable in-line spectroscopic techniques for measuring product residual moisture content and vapor flow rate and distributed sensors for wireless measurement of temperature. There are also challenges in the development of dynamic models of sufficient fidelity that can quantify the effect of process variations. The most important technical challenge related to process control is to achieve ice nucleation that has consistent ice crystal structure and uniform drying rates.

The key challenge for continuous lyophilization is to increase heat- and mass-transfer rates so as to reduce the required residence time and thus required equipment volume for the sequential stages of primary and secondary drying. Real-time image processing of vials during and at the end of processing for quality control that is of sufficiently high resolution is important for uniformity in process monitoring. The mechanical complexity of vial handling for spinning and the effect of infrared and micro-ware heating on product degradation also pose technical challenges.

The critical technical challenge related to spray freeze-drying is to provide enough residence time to achieve the desired reduction in moisture while avoiding particle agglomeration. Particle-size distribution needs to be controlled to achieve good powder flow for efficient vial filling.

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¹ See https://pharmahub.org/groups/lyo/lyohub_roadmapping.

Regulatory Challenges

The regulatory challenges associated with PAT, process modeling, and closed-loop control of batch operation in these technologies do not appear to be much different from those associated with their implementation in other pharmaceutical manufacturing contexts, as discussed in Chapter 4 of this report. One regulatory challenge is to find a pathway for approving a new processing technology as a platform independent of a particular product filing. Another challenge is that improving a lyophilization technology that is being used to produce an approved product—for example, with microwave vacuum drying—requires filing a major supplement or variation, including extensive product characterization data, in every country in which it is approved.

Aseptic Manufacturing

Whether or not a product is lyophilized, it needs to remain free from microbial contamination during filling of vials, syringes, or cartridges. Contamination during processing occurs from surfaces and airborne sources. Given that people are one of the primary sources of contamination, the key innovation is to eliminate the operator from the process by using fully automated processes enclosed in an isolation chamber. Accordingly, the innovative technology is a gloveless, robotic aseptic filling work cell that uses single-use disposable components. The integrated filling operation is carried out in an isolator unit in which handling is accomplished by using robotics. The isolator unit can be effectively decontaminated, and an important source of integrity failure can be eliminated by removing the gauntlet gloves. Robust automation also enables efficient production of small batches.

Technical Challenges

The key technical challenges lie in continuous environmental monitoring to ensure aseptic conditions and in the design of robust automation technology. Robotics adds the complexity of software development, validation, and maintenance and the requirements for condition-based monitoring and maintenance. The inflexibility of robotic technology to increase volume or batch size (larger numbers of vials, syringes, or cartridges) to meet commercial demands likewise presents an implementation challenge.

Regulatory Challenges

The main regulatory challenges are associated with the extensive effort required for the initial and continuous validation process, including the established mandate of an aseptic process simulation for every combination of container, closure, fill volume, and batch size. Another regulatory barrier is the requirement for extensive environmental monitoring even though the operator is no longer part of the filling process. The degree of monitoring should be based on an assessment of the expected contamination risks.

ENABLING NEW FORMS OF DRUG PRODUCTS

As innovations in drug-product forms or compositions are being developed, the hope is that the new modalities provide increased absorption, convenience, compliance, and efficacy. Manufacturing efficiencies are also expected as new processes are developed. The drug-product innovations will most likely be common in the next 5–10 years as manufacturing processes for the new forms are refined. The three forms presented in this section—the microparticle, nanoparticle, and extracellular vesicles—are still relatively new areas of drug-product development. Such complex formulations are often referred to as “products by process” because they have quality attributes that are determined largely by their manufacturing process. The technologic and regulatory challenges that are associated with these products are described at the end of this section.

Microparticles

Microparticles are small, free-flowing entities that have particle diameters of 1–1,000 μm. They hold great promise as drug-delivery systems because of their ability to encapsulate water-insoluble and sparingly water-soluble agents with the potential to deliver an active agent in the right amount, at the right time, and to a desired location in the body in a manner that minimizes side effects. Microparticle drug-delivery systems come in many varieties, including micropellets, microgranules, microspheres, microcapsules, microsponges, and liposomal preparations. Their benefits stem from the unique and often tunable microparticle properties, including size, shape, structure, drug loading, entrapment efficiency, porosity, and release profile. Regarding size, microparticles are advantageous because they do not traverse into the interstitium and thus can act locally with prolonged effects. From a drug-loading perspective, microparticles can shield an API from environmental conditions (such as temperature, pH, oxidation, and proteolytic degradation) and can protect the body from harmful side effects of the API (such as irritation, mucosal damage, and cell

toxicity). From a formulation standpoint, microparticles can be incorporated into various pharmaceutical dosage forms, such as liquids (solutions, suspensions, and parenterals), semisolids (gels, creams, and pastes), and solids (capsules, tablets, and sachets).

The mechanism of drug release from microparticles (dissolution or diffusion, osmotically driven release, and erosion) is an important design criterion and is often the direct result of innovative manufacturing technologies or novel excipients. The most commonly used excipients in microparticle delivery systems are biopolymers of plant, animal, or microbial origin (Lengyel et al. 2019), although semisynthetic and synthetic polymers (biodegradable or nonbiodegradable) are also gaining attention (see section below on novel excipients). Production processes used to generate microparticle delivery systems include spray-drying, extrusion, coacervation, freeze-drying, emulsification, precipitation, crystallization, and microfluidics and possibly the innovative approaches discussed in the sections above. For example, novel microfluidic systems have proved advantageous for microparticle production, and various methods for engineering microparticles are emerging, such as continuous-flow–based and electrowet-ting-based droplet generators (Damiati et al. 2018). Another emerging approach inspired by the semiconductor industry involves continuous-flow lithography, in which a monomer solution of a photopolymerizable material (such as polyethylene-glycol-diacrylate) is pumped through a microfluidic device in the presence of light.

A promising example of a microscale bead product is development of the lyosphere. Beads formed from a liquid formulation of API and excipients are manufactured in an innovative process whose first step involves rapid freezing of drops of the formulation as they are deposited from an automated nozzle onto an ultracold metal plate (Kapoor et al. 2020). The individual frozen beads are then transferred to a freeze dryer in which they undergo the conventional multistage freeze-drying process in bulk. The key difference from conventional lyophilized material is that the result is a bead rather than a dried powder. The lyospheres produced must be analyzed for potency and titrated into the final drug-product vial to obtain the target dose (Barr et al. 2019). The possibilities of bulk dry bead storage and the ability to change the amount of lyospheres per vial provide supply chain flexibility and the flexibility to use new drug-product presentations and device opportunities. The technology has the potential to improve the thermal stability profiles of products, and it is envisioned that custom medicines could be made by using this technology.

Nanoparticles

Nanoparticles are microscopic particles less than 100 nm in diameter and include liposomes, polymers, nanocrystals, proteins, and other nanoscale molecules with applications in oncology, neurology, immunology, anti-infective materials, and cardiovascular therapeutics. Nanotechnology has opened the door to the development of nanopharmaceuticals. The new formulations are intended to overcome problems related to drug solubility or pharmacokinetics and pharmacodynamics profiles, improve the drug-release profile, or reduce toxicity or adverse side effects. The biodistribution and blood-circulation half-life of nanoparticles also can be adjusted depending on the route of administration (Alexis et al. 2008).

In nanopharmaceutical formulations, the selected drug type is encapsulated in a polymer, lipid, protein, or metal matrix. Once the matrix is determined, scale-up and quality assurance of the selected production methods are studied for commercial production. A clear understanding of clinically compliant production methods is an important regulatory concern. Many emerging nanopharmaceuticals have been proposed to improve the therapeutic outcome of the use of multiple drugs and biomolecules and to tackle unmet medical needs. However, because of the difficulties that are typically encountered in process scale-up to meet product quantity and quality requirements for clinical trials, few nanopharmaceuticals are on the market. Production at scale is a serious challenge (Souto et al. 2020a).

Various innovative production methods are used depending on the nanoparticle types. High-pressure homogenization, membrane contractor, microemulsion, multiple emulsion, and solvent emulsification diffusion are a few methods used for lipid nanoparticles. Extrusion, ionic gelation, nanoprecipitation, salting-out, and the use of supercritical fluid are a few production methods for polymer nanoparticles. Chemical and physical methods are used to produce metal nanoparticles.

One innovative technology that has enabled new ways to manufacture nanoscale drug products is microfluidics. It is extremely useful for controlled synthesis of drug-loaded nanoparticles because it provides precise fluidic modulation and enhanced mixing, is low cost, and is readily designable. A major benefit of the enhanced mixing process involved in microfluidics is that it occurs much faster than the nucleation process of nanoparticles; this allows for production of large quantities of nanoparticles with a narrow size distribution. Research has revealed that slight alterations of the mixing strategy, microfluidic device assembly, and post-synthesis surfaces can influ-

ence the functionality and biologic effects of microfluidics-assembled nanoparticles. The functionalities and biologic effects tend to improve with the use of microfluidic devices, compared with nanoparticles produced by bulk methods (Feng et al. 2016).

Nanoparticles synthesized with biodegradable polymers are most preferred for drug-delivery systems, and lipid-shell polymer core hybrid nanoparticles are the most extensively studied nanodelivery systems. Often compared with liposomes because of their solid core structure, lipid-shell polymer nanoparticles offer biocompatibility, the ability to encapsulate different types of drugs, and high loading efficiency (Allen and Cullis 2004; Jiang et al. 2010). They can be prepared in a high-throughput manner by using microfluidic principles. The confined impingement jet mixer is a type of microfluidic device that prepares nanoparticles via flash nanoprecipitation (Johnson and Prud’homme 2003). During flash nanoprecipitation, a hydrophobic drug and an amphiphilic block copolymer (such as polyethylene glycol-b-polylactic acid) are co-dissolved in an organic solvent (such as tetrahydrofuran) and turbulently mixed with water through high-velocity impingement. The supersaturation of the drug–copolymer mix with the antisolvent water stimulates co-precipitation of nanoparticles within milliseconds (Han et al. 2012). Further enhancements of the microjet reactor have been made over the years, such as equipping it with a confined impinging jet, which has recently allowed innovative ciprofloxacin-loaded poly(DL-lactide-co-glycolide) nanoparticles to be produced. Nanoparticles fabricated with that method were shown to have a greater therapeutic effect with continuous and localized slow release of a highly concentrated antibiotic (Günday et al. 2020).

Overall, nanotechnology-based drug products hold tremendous promise because of their favorable size, shape, structure, and surface properties. However, maintaining their quality, safety, and efficacy over the course of the scale-up process poses a substantial challenge. Because these drug products are still relatively new and their manufacturing processes are emerging, a Quality by Design approach to gathering deep product and process understanding is needed.

Extracellular Vesicles

The release of extracellular vesicles (EVs) is a conserved cellular process that occurs in Archaea, Bacteria, and Eukarya. EVs deliver various molecular cargoes through fusion or endocytosis and modify the recipient cells’ physiology. Because they are small, they can be passively delivered anywhere in the body, and their status as natural cellular products means that they are likely to cause relatively few undesirable immune reactions. Their composition and origin determine their intrinsic targeting properties, and they can cross biologic barriers and deliver their cargoes to recipient cells with virus-like efficiency; this makes them highly attractive as drug-delivery vehicles (Johnsen et al. 2014).

EVs are differentiated on the basis of their intracellular origins. One major type, microvesicles (MVs), is formed through the outward budding and fission from plasma membranes and range in size from 50 to 1,000 nm, depending on the producing cell. MVs are also referred to as microparticles, shedding vesicles, plasma membrane-derived vesicles, ectosomes, and exovesicles; however, to avoid confusion and promote standardization of nomenclature the term microvesicle has gained favor. From a drug-development standpoint, MVs derived from the outer membranes of bacteria—known as outer-membrane vesicles (OMVs)—have garnered substantial attention as vaccines and have attained U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval of the meningococcal group B (MenB) vaccine Bexsero, which contains 25 μg of OMVs derived from the bacterium Neisseria meningitidis serogroup B. Although bacterial OMVs are not as advanced for delivering drugs, several companies and many academic researchers are exploring their use as an innovative way to deliver small-molecule and large-molecule drugs.

The other major category of EVs is exosomes, which differ from MVs mainly in size and intracellular origin. Exosomes are 50–150 nm in diameter, are secreted by all mammalian cells except mature red blood cells, and are involved in diverse physiologic and pathologic functions in the body. In contrast with MVs, exosomes are formed in the cytosol by tightly controlled inward budding into large multivesicular bodies that can then fuse with the plasma membrane and release exosomes into the extracellular space. Perhaps most relevant to drug development is the fact that exosomes can serve as vehicles to transfer membrane and cytosolic proteins, lipids, and RNA between cells and thus provide an important mode of intercellular communication. Because of their innate ability to transfer RNA (such as mRNA and miRNA) and proteins to recipient cells, exosomes have been exploited as novel drug-delivery agents for targeted treatment of various diseases.

Exosomes can be easily harvested from various cell types, and current research is focused on determining the optimal host cells from which to derive exosomes and on engineering them to host the desired therapeutic agent (Bunggulawa et al. 2018). To investigate functional

characteristics of various exosomes, researchers have isolated exosomes from macrophages, metastatic cancer cells, pancreatic cancer cells, and tumor-derived cells. It is worth noting that exosomes and MVs, although distinguishable by their origin, are rarely distinguishable in practice, and this might pose characterization challenges when it comes to manufacturing these entities.

Research has shown that different types of exosomes can stimulate immune systems differently, have different safety profiles, and have a host of other different biochemical properties, such as degradation. Ultimately, the exosome type is chosen on the basis of the desired therapy and which API needs to be delivered. As noted, exosomes can be loaded with a variety of therapeutic agents to achieve a desired functionality on delivery to a patient. An API can be loaded into exosomes by a few methods, including incubation, freeze–thaw cycling, and electroporation. Each method has advantages and disadvantages with respect to safety and loading efficiency and needs to be selected for each specific application. Exosomes will help to usher in a new generation of drug delivery as research efforts in large-scale manufacturing continue.

Technical Challenges

The major challenges in producing the new particulate product forms at scale are to develop reproducible manufacturing processes and characterization methods, to ensure in vivo stability, and to manage the biophysical and chemical properties of their formulations. Advances in in-line sensors for critical quality attributes, process automation, and innovations in the engineering design of the microfluidic systems themselves are needed to speed the advancement of these pharmaceutical drug products (Agrahari and Agrahari 2018). The slow pace of traditional empirical development methods for these products also needs to be increased by using process models and integrating first principles with data-driven components where gaps in fundamental knowledge remain.

Regulatory Challenges

Major regulatory challenges include guaranteeing drug safety, efficacy, and stability during scale-up; increasing familiarity with new unit operations; and ensuring adherence to current good manufacturing practices (Leaver 2017). No defined specifications or guidelines have been published to assist drug developers in understanding what justification is required to ensure that the new unit operations provide safe and efficacious new drug forms. In addition, the critical quality attributes for these new types of drug products are not well understood, and this makes it difficult to set product specifications and design process-control strategies.

ENABLING NEW DRUG-PRODUCT FORMULATIONS: NOVEL EXCIPIENTS

The U.S. Pharmacopeia Convention (USP) defines excipients as “substances other than the active pharmaceutical ingredient…that are intentionally included in an approved drug delivery system or a finished drug product” (USP 2016, p. 3). They are typically added during formulation operations after the production of a drug substance and can often account for up to 90% of the mass of the resulting drug product. They are used to perform diverse functions, such as facilitating or enabling the production of the drug-delivery system; protecting the drug against degradation during processing, storage, or delivery; increasing the effectiveness of the drug by increasing its solubility or bioavailability; providing a means for product identification; and improving the safety, acceptability, and abuse deterrence of the drug. Unlike APIs, excipients can have complex compositions—for example, heterogeneous mixtures of related compounds, such as polysorbates—and might not have been designed or manufactured specifically for use in pharmaceuticals, such as compounds that were originally created for food and cosmetic applications.

The selection of excipients for a given drug substance depends heavily on precedent. FDA maintains a list of excipients that have been used in approved drugs, the Inactive Ingredients Database (IID),² that is updated quarterly. A manufacturer can make a regulatory filing for a drug product that includes one or more excipients without having to demonstrate excipient safety as long as the excipients appear in the IID and are used in amounts no greater than the listed amounts per dose for the given route of delivery. By using IID-listed excipients, manufacturers reduce the time, cost, and risk associated with regulatory filings. Manufacturers have become adept at side-stepping the introduction of new excipients by creatively using combinations of listed excipients to address formulation challenges posed by new molecular entities. For example, the number of excipients used in approved monoclonal antibody (mAb) drugs ranges from one to 13, with an average of four, including buffer species, salts, sugars and surfactants (Seymour 2020).

A manufacturer, however, might prefer to use a new excipient to solve a specific drug-product production or

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² See https://www.fda.gov/drugs/drug-approvals-and-databases/inactive-ingredients-database-download.

formulation problem that is not well addressed by IID-listed excipients.³ The introduction of a novel excipient is a manufacturing innovation that changes stream composition and molecular-level interactions with an API compared with conventional formulations and that might be accompanied by or necessitate further innovation in manufacturing unit operations, PAT, or process control strategy. It is currently expected that new excipients would be introduced at the investigational new drug (IND) stage with safety data on each new excipient that is used with a new molecular entity. Reasons for the use of a new excipient include newly understood limitations of members of a given class of IID-listed excipients, the increased complexity of new drugs and dosage forms, and the needs of new types of manufacturing unit operations (IPQ 2020).

Our understanding of the stability and metabolism of commonly used excipients has revealed limitations within the IID. For example, polysorbate 80 is a common surfactant used in high-concentration mAb formulations. It has been shown that trace amounts of esterase enzyme impurities in an mAb drug substance can catalyze the degradation of the surfactant, including reduction of its interfacial activity (Larson et al. 2020). New, alternative surfactants have been developed by several excipient manufacturers to address the limitations of IID-listed hydrolyzable surfactants (Soane et al. 2018; Katz et al. 2019). Other limitations of current excipients include unsuitability for use in pediatric patients because of metabolic pathways that differ from adult pathways and poor performance of enteric coatings for protection of biologics.

The increasing complexity of new molecular entities is also driving the need for enabling excipients. For small-molecule drugs, the conventional rule of thumb that API molecular mass should be kept below 500 Da (Lipinski et al. 1997), and even the whole notion of a “small-molecule drug” is steadily challenged by the pursuit of large macro-cyclic and oligonucleotide targets with molecular masses that can exceed 9 kDa (Selwood 2017; Tom 2020). Such high-molecular-weight, high-complexity small-molecule drugs can pose substantial concerns regarding solubility, chemical stability, or physical stability that must be addressed with excipients. For example, solubility issues might be overcome with novel lipid-based excipients, polymeric amorphous stabilizers, or macrocycles that are capable of forming host–guest complexes (Havel 2018; Selwood 2017). Oligonucleotides have multiple tissue barriers, cellular targeting and uptake issues, and intracellular trafficking hurdles that a formulation must overcome, driving innovations in both excipients and drug-product forms, as described above (Juliano 2016). As discussed in Chapter 2, antibody–drug conjugates (ADCs) represent the juncture of the small-molecule and biologic drug formulation worlds and creation of an extremely high-potency class of drug species. Premature scission of the conjugate is a serious delivery concern, given the lethality of the “warhead” component of the ADC. There is a strong driver for moving beyond the repertoire of excipients currently used to stabilize mAb therapeutics to new excipients that can chemically and physically stabilize these purposely labile conjugates until they reach the targeted site, and stabilizing these new modalities might provide additional, less-invasive routes of delivery beyond the current intravenous-infusion route (Alves 2019).

New dosage forms and corresponding new routes of delivery, motivated by the desire to reduce invasiveness or to localize treatments, are also driving the development of enabling excipients. As mAb routes of administration migrate from intravenous infusion to subcutaneous and intramuscular injection to reduce patient risks and simplify administration, the mAb concentration is increased (100 mg/mL or greater) to accommodate the necessary mass dosages in a much smaller administration volume. The increased concentration results in increased formulation viscosities that can make injection difficult or impossible. New excipients, such as hydrophobic salts, have been identified that can dramatically reduce high-concentration mAb formulation viscosity (Ke et al. 2018). Other alternatives for delivery of biologics—such as oral, transdermal, nasal, and pulmonary routes—are in various stages of active preclinical development with new small-molecule, polymeric, and peptidic excipients to serve as enteric coatings, permeability enhancers, mucoadhesives, enzyme inhibitors, transport enhancers, cell penetrators, and tight-junction modulators (Anselmo et al. 2019). Beyond the route-based needs, new excipients might be required for the development of implantable delivery devices and drug-delivery device combinations (IPQ 2020).

Finally, the use of new types of equipment in the manufacture of drug products, such as hot-melt extruders (HMEs) and twin-screw granulators, presents opportunities and needs for new excipients. In an HME, an API with poor solubility or bioavailability is dispersed in an amorphous or crystalline solid state into a polymer melt and extruded in a water-free or solvent-free process to produce a solid that can be milled or pelletized to form

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³ FDA defines new excipients as “any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration” (FDA 2005, p. 1).

tablets, capsules, and sustained drug-delivery depots. Beyond the high concentration of polymeric excipient used in HMEs, which itself might lead to the “new excipient” classification, new plasticizing excipients might be needed to manipulate the solid-phase solubility of the API in the polymer, and new solubilizers might be needed to manage the crystallization of amorphous API solids on release in the digestive tract (Simões et al. 2019). Twin-screw wet granulation is gaining traction as a continuous unit operation that allows wetting and nucleation phenomena to be controlled separately from consolidation and growth phenomena (El Hagrasy et al. 2013) and provides narrow material residence-time distributions (Shirazian et al. 2018). The method provides access to a wide array of particle structures with narrow property distributions. The key excipients in the granulation-step case are fillers to add bulk and binders to provide structural integrity to the consolidated solids; these excipients are augmented with powder flowability, lubrication, and disintegration agents during later tableting operations (Willecke et al. 2018). There are opportunities for new lower-viscosity binder liquids and fillers that have lower compressibility. New, continuous manufacturing formats might also provide opportunities for new excipients.

Technical Challenges

Regardless of the driver for the introduction of novel excipients by a manufacturer, the result is a new stream composition that persists through the formulation and filling operations. The safety and efficacy of a novel excipient that is truly distinct from IID excipients will always need to be demonstrated, regardless of current or future regulatory pathways. Possible interactions between the novel excipients and the trace components in the drug-substance stream, which might fluctuate in type and amount, might directly affect the drug-product manufacturing process. For example, novel excipients might be subject to attack by unidentified trace host enzymes and lead to loss in drug-product stability or performance, or degradation byproducts might lead to the formation of aggregates or haze. Thus, an enabling novel excipient might require host-cell engineering or downstream process modifications. Incorporation of novel excipients also might require changes in the unit operations used in formulation and filling. When used in high proportions relative to the API, such as polymeric excipients used in HMEs, novel excipients might present substantial blending and drug-product uniformity challenges that require novel blending equipment. Finally, novel drug-product stream compositions might require novel sensors and control strategies for process monitoring and control during formulation and filling operations.

Regulatory Challenges

The main regulatory challenge associated with the introduction of new excipients is that they are approved with the new molecular entity; there is no mechanism for approval of new excipients in isolation. Manufacturers must assume the combined time, costs, and risks associated with demonstration of the safety of a new excipient and pharmacologic effects in addition to the demonstration of the safety and effectiveness of the drug product

(FDA 2005). That challenge has long been recognized by industry and is the subject of a recent USP survey (see Box 3-1). It is clear that manufacturers might forgo the use of a novel excipient even when there are potential public health benefits. Several promising novel excipients have had no market uptake because of real and perceived regulatory barriers, and there are examples of formulations marketed elsewhere but not available for use in the United States because of novel excipient status (IPQ 2020). The challenges associated with the introduction of a new excipient in a drug product are mirrored to some extent by the challenges posed in introducing new biomaterials in medical devices.

For the novel excipient category, industry consortia and trade organizations—such as the joint Novel Excipients Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development and the International Pharmaceutical Excipients Council—are working with FDA to address the new excipient regulatory barrier (IPQ 2020). In February 2020, their efforts culminated in an FDA solicitation of comments on a proposed standalone novel excipient review pilot program designed to decouple novel excipient review from IND, new drug application (NDA), or biologics license application (BLA) reviews.⁴ Under the proposed pilot program, “recognition” of a novel excipient by FDA could eliminate the need to review the excipient separately within an IND application. At the NDA or BLA stage, the safety of the finished drug product would be evaluated when “recognized” excipients are included. The intent is that approval at the NDA or BLA stage would lead to the novel excipient’s inclusion in the IID and thus facilitate more widespread adoption. The rapid institution of the proposed pilot review program should encourage the introduction of novel excipients by streamlining regulatory filings for new molecular entities that involve novel excipients.

Another important regulatory barrier is the lack of international concordance in the approval process for novel excipients. There are substantial differences even in how a novel excipient is defined; an excipient treated as recognized in one jurisdiction because of its use as a food or cosmetic additive might be classified as novel in another jurisdiction. That deviation in regulatory practice has a chilling effect on innovation because a manufacturer who has global marketing intentions will formulate to the lowest common denominator.

Finally, although the IID concept is meant to enable rapid development of new drugs when established formulations are adopted for new drugs, the IID inherently encourages manufacturers to use outdated technology. The reality is that new drugs might use 20-year-old formulation technology and forgo potential performance improvements in favor of regulatory certainty and expediency. A special case arises for innovations in formulations for generics and biosimilars. Manufacturers might be locked into older formulations and compositions in an abbreviated NDA or abbreviated BLA even though new excipients might offer substantive performance enhancements (IPQ 2020). Unfortunately, old formulations of legacy drugs are essentially locked in permanently.

OVERCOMING REGULATORY CHALLENGES

As new technologies for manufacturing drug products advance in the pharmaceutical industry, early and frequent interaction with FDA is the most basic fundamental method for overcoming regulatory challenges. As noted in Chapter 1, the establishment of the Emerging Technology Team has been instrumental in opening doors for conversations with FDA so that companies investing time and effort in uncharted territories can share their plans and receive feedback. The more these conversations allow open brainstorming, discussion of “what if” scenarios, establishment of expected outcomes, and education of both sides, the smaller the chance that surprises will curtail a novel technology. For drug products, such surprises are especially problematic for two reasons: (1) at this point, the product is closer to the stage of administration to a patient, and failure is not an option inasmuch as it could have devastating effects, and (2) investment by and cost to the company has been compounded as the product has progressed through the entire drug-development pathway. Failure to consider something that FDA found to be critical could shut down a project and potentially put a small company out of business. Some suggestions for overcoming the regulatory challenges that are specific to this chapter are provided below. More general and overarching recommendations are provided in Chapter 6.

• Develop mechanisms for evaluating a technology or platform outside individual product submissions. Although not fully analogous, the principle outlined in the proposed pilot program for the toxicologic and quality evaluation of novel excipients might provide a useful illustrative example to consider more broadly for drug-product manufacturing technologies. For example, a mechanism to consider additive manufacturing platforms

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⁴ “Novel Excipient Review Program Proposal; Request for Information and Comments,” Federal Register, 84(234), 66669-66671, 5 Dec 2019.

• could guide the demonstration of their capability to deliver consistent, high-quality drug products suitable for registration reproducibly. That approach would lower the risk of implementation broadly for industry and accelerate use within an individual product submission in the future.
• Harmonize among several international regulatory agencies. Applying for approvals in multiple countries after implementing an innovative process can be expensive and time-consuming. It can often result in the presence of multiple versions of the same product on the market until all the applicable countries have approved the innovation. Developing programs similar to the European Mutual Recognition Procedure or expanding more programs like FDA’s Project Orbis would be helpful to the industry and render the regulatory approval process by multiple regulatory bodies less inhibitive.
• For such new delivery formats as microparticles and nanoparticles, the industry needs regulatory guidelines so that developers and innovators have clarity on how to scale up and show equivalent characterization. There is a need for specifications or strategic guidelines for such technologies, and there is little regulatory guidance in this respect. There is no international definition of what these materials are, and this lack affects research and development funding adversely and destroys public acceptance and perception of the novel drug-product forms (Foulkes et al. 2020; Souto et al. 2020b).
• Additional regulatory changes might also facilitate the development and adoption of new excipients. For example, the granting of a period of exclusivity and concomitant development of a USP and National Formulary monograph for novel excipients might spur excipient manufacturers and drug manufacturers, respectively. The inclusion in the IID of a section that describes new excipients under development or consideration might spur earlier adoption by other manufacturers. For manufacturers of generics and biosimilars, relaxation of the requirements for similarity with the original formulation could provide important patient and manufacturability benefits. Finally, as mentioned previously, work is needed to harmonize the regulation of excipients among jurisdictions.

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