key: cord-0716111-54ezqiwz
authors: Gutierrez, Lucas; Cauchon, Nina S.; Christian, Twinkle R.; Giffin, Mike; Abernathy, Michael J.
title: The Confluence of Innovation in Therapeutics and Regulation: Recent CMC Considerations
date: 2020-09-21
journal: J Pharm Sci
DOI: 10.1016/j.xphs.2020.09.025
sha: 96d18253a7434a083474b2e6b6005b4fa548c54e
doc_id: 716111
cord_uid: 54ezqiwz

The field of human therapeutics has expanded tremendously from small molecules to complex biological modalities, and this trend has accelerated in the last two decades with a greater diversity in the types and applications of novel modalities, accompanied by increasing sophistication in drug delivery technology. These innovations have led to a corresponding increase in the number of therapies seeking regulatory approval, and as the industry continues to evolve regulations will need to adapt to the ever-changing landscape. The growth in this field thus represents a challenge for regulatory authorities as well as for sponsors. This review provides a brief description of novel biologics, including innovative antibody therapeutics, genetic modification technologies, new developments in vaccines, and multifunctional modalities. It also describes a few pertinent drug delivery mechanisms such as nanoparticles, liposomes, coformulation, recombinant human hyaluronidase for subcutaneous delivery, pulmonary delivery, and 3D printing. In addition, it provides an overview of the current CMC regulatory challenges and discusses potential methods of accelerating regulatory mechanisms for more efficient approvals. Finally, we look at the future of biotherapeutics and emphasize the need to bring these modalities to the forefront of patient care from a global perspective as effectively as possible.

The field of human therapeutics has drastically expanded from small molecules to complex biological modalities, and this trend has greatly accelerated in the last two decades with significant diversity in the types and applications of novel modalities. Innovations in the development of novel modalities are accompanied by an increase in the sophistication of drug delivery technology that has further enhanced the pharmacological space. Additionally, the pharmaceutical industry is currently adapting to a "data explosion", but the full and effective utilization of big data is very much in its infancy relative to the technology sector. It is a considerable challenge to manage the inordinate amount of data generated and to integrate the data efficiently across the various disciplines. Innovation in novel modalities has led to a substantial increase in the number of therapies seeking regulatory approval, with more data being generated than ever before. As the industry continues to evolve, regulations will need to adapt accordingly to accommodate a continuously evolving landscape. The growth in novel modalities represents a challenge for regulatory authorities, as their goal is to provide a timely assessment of the safety, efficacy and quality of these new modalities. The speed of these assessments is a critical factor, as patients are in urgent need of lifesaving treatments.

Historically, for most of the 20 th century, small molecules and some biologics, such as insulin and monoclonal antibodies (mAbs), constituted the majority of approved therapeutics. However, as pharmaceutical development continued due to advancements in scientific achievements, more complex biologics have demonstrated clinical efficacy in various therapeutic areas, prompting regulatory authorities to draft additional guidance accordingly. In the current pharmaceutical landscape of accelerated complex protein engineering that allows for the mixing and matching of multiple biologics, an increasing number of novel modalities are being developed which lack any prior regulatory filing experience. The lack of regulatory precedence with new modalities provides an uncertainty for some regulatory requirements which may hinder regulatory approval. An ever-present challenge for innovators is a lack of background knowledge and expectations of reviewers and health authorities, which can vary by jurisdiction and in some cases, may rely on historical paradigms that may not be relevant for new modalities. This becomes a progressively more complex issue with live modality biologics, such as viralor cell-based modalities for which quality attributes are poorly defined and current testing technologies are poorly suited. In the age of personalized medicine, this uncertainty will become an increasingly common theme, as technology will be capable of identifying specific biological attributes in patients and tailoring therapies to address heterogeneous diseases. Future product platforms will consist of a high product mix and low volume output production paradigm. Therefore, global regulations must evolve to keep pace with pharmaceutical innovation and even anticipate certain developments ahead of their liposomes, human hyaluronidase PH20 enzyme, pulmonary delivery, and 3D printing. We will also discuss current clinical applications of these technologies, as well as some of the manufacturing issues associated with them.

2. Provide a brief understanding of the regulatory framework that is currently in place to evaluate these modalities with an emphasis on chemistry, manufacturing and controls. We will also discuss regulatory challenges that manufacturers are currently encountering in the development of these modalities.

3. Discuss specific forward-looking trends in regulatory science that could potentially ameliorate the aforementioned challenges, including the development of accelerated regulatory approvals and the harmonization of guidelines for international regulatory authorities. 4 . Provide regulatory recommendations that may address future issues and describe our view of some long-term manufacturing developments that will occur in the future regarding personalized medicine.

There is an ever-expanding range of novel modalities of diverse functions, indications and compositions that are in development. Some of these new modalities are under clinical investigation in late-phase trials with the number of approvals expected to increase exponentially. This section provides a brief overview of some of the most promising novel biologic modalities including novel antibodies, gene therapy, vaccines and multifunctional modalities.

Bispecific antibodies (BsAbs) and their derivatives represent an extension of monoclonal antibody biotechnology that can specifically target multiple antigens to elicit a range of biological effects. binding potential and have a strong affinity to their cognate antigen. One of the advantages of using nanobodies over mAbs is their small size, which allows for increased vascular permeability and retention effect as well as poor lymphatic drainage, which aids in achieving drug accumulation into the tumor microenvironment (TME). 7, 8 In 2019, Sanofi's caplacizumab was the first nanobody to receive FDA approval for the treatment of acquired thrombotic thrombocytopenia purpura. 9 Researchers have also shown that nanobodies can be conjugated with various components such as drugs or radionuclides for targeted therapy. For example, one group created nanobody-liposomes that recognize the ectodomain of EGFR and tested it in vivo to find that this modality resulted in a significant inhibition of tumor cell proliferation. 10 Therefore, in the future, it is possible that we may see additional novel therapeutic nanobodies used in the clinic and potentially patient care.

Antibodies are one of the largest classes of therapeutic proteins in the biopharmaceutical industry, but their intended action can be limited in solid tumors due to on-target off-tumor effects caused by binding to the target molecule on non-malignant cells. 11, 12 Masking antibodies are antibody prodrugs that take advantage of tumor-specific protease activity for activation, thereby limiting drug activity in healthy tissues. 13, 14 They are comprised of a monoclonal IgG antibody or fragment that targets the tumorassociated antigen and a masking peptide linked by a protease-cleavable substrate linker peptide. The tumor-specific proteases will cleave the peptide linker, thus relieving the masking activity and allow the J o u r n a l P r e -p r o o f antibody to bind to the target cancer cells. CytomX Therapeutics has developed masking antibodies that are undergoing various stages of clinical trials targeting diseases such as breast cancer. 15 

Designed ankyrin repeat proteins (DARPins ® ) have a hypervariable loop to engineer specific protein-protein interactions selected by phage display, are genetically engineered proteins that are smaller than antibodies, and recognize targets with improved affinity, resulting in superior tissue penetration. 16 The developmental and manufacturing-related advantages of DARPins include resistance to aggregation, high expression in E. coli vectors, and adaptable protein engineering allowing the capability to target 3 proteins simultaneously. 17, 18 Companies such as AbbVie, Amgen and Molecular

Partners have DARPins that are undergoing various stages of clinical development. 19 

While innovation of antibody modalities represents critical and clinically important developments in biologic therapeutics, cell-based therapies, such as CAR T cells, have also made notable advances throughout the recent past. A chimeric antigen receptor (CAR) is an engineered receptor comprised of an extracellular antigen-recognition domain targeting a specific antigen, an intracellular CD3-zeta T cell receptor signaling domain that activates T cells upon antigen binding, and typically a co-stimulatory domain (often CD28 or 4-1BB) to enhance T cell function, leading to target cell lysis as well as T cell proliferation and cytokine secretion. Clinical success of this technology has led to the approvals of Novartis' Kymriah ® , Gilead's Yescarta ® , and more recently Gilead's Tecartus ® . 20, 21 Current innovation in this field seeks to improve the functionality of CAR T cells in light of issues such as the oftenimmunosuppressive TME, an obstacle in the treatment of solid tumors because of the many mechanisms that cancer cells can utilize to prevent the CAR T cells from functioning appropriately. 22, 23 New engineering designs that incorporate additional immunomodulatory payloads into the engineered cell product are entering clinical trials, such as a Phase I CAR design in which the extracellular portion consists of the IL-4 alpha subunit combined with an intracellular IL-2/IL-15 beta subunit, thereby utilizing IL-4 in the TME to activate T cells. 24 Another change being explored clinically is the switch from engineering T cells to natural killer cells, as they do not exhibit the same safety complications, such as off-target effects or cytokine release syndrome; do not undergo cell exhaustion; and could potentially be used in an allogeneic setting.

manufacturing process fast as possible, as they are in a race against time to provide therapy to a patient that no longer has other treatment options. It is possible that material quality attributes and process controls may improve cell product manufacturing, as the relationship of these attributes and process parameters on final product quality become more apparent.

Genetic engineering is the modification of DNA through insertion, deletion or the replacement of CRISPR Therapeutics respectively for the manufacture of CAR T cells. 26, 27 Specific manufacturing issues that may arise during production and implementation of genetic editing technology include the targeted delivery of the genes to the intended tissues to reduce the risk of deleterious off-target effects. To limit the development of off-target effects, manufacturers will need to employ methods to mitigate the reduced fidelity of the CRISPR system to improve the safety profile of the therapy. 28, 29 In addition to off-target effects, many manufacturers make use of viral vectors as a means of transferring the genetic material necessary for gene editing; however, they can present with unwanted effects in patients, such as immunogenicity.

Vaccines have been widely successful in improving human health, and although the field of research is too large for the scope of this review, recent improvements in vaccine technology should be highlighted. For example, certain nanoparticle formulations have been demonstrated to protect vaccine components from premature degradation, improve stability, and have enhanced adjuvant properties. 30 Moderna's mRNA-based SARS-CoV-2 vaccine, which uses a lipid-nanoparticle formulated vaccine, is currently undergoing Phase III trials for the treatment of COVID-19. 31 In addition, researchers are making efforts towards the development of cancer vaccines, however, these can be difficult to design because the immune system is generally adapted to target non-eukaryotic pathogens. Despite this, cellular vaccines that utilize an individual patient's tumor lysate loaded onto antigen-presenting dendritic cells to elicit a strong T cell response from patients are also currently being investigated in clinical trials. 32, 33 Vaccine manufacturing can be a challenging endeavor, as the final product can suffer from inherent variability in both starting material and assays used to demonstrate quality.

J o u r n a l P r e -p r o o f

Multifunctional modalities combine different modality types through either fusion or conjugation, thereby modulating potency and cellular uptake as well as improving the accuracy of cell delivery. Of these two methods to generate a multifunctional modality, conjugate modalities seem to be utilized more frequently, and function by either synergizing the pharmacological activity of both components or improving the function of one modality via the function of another. 34 One of the more successful multifunctional modalities that exist are antibody-drug conjugates (ADCs), which are composed of a highly specific targeting antibody, a cytotoxic agent, and a linker to combine the two elements. 35 Many

ADCs have already been approved, with a recent example being McKesson's sacituzumab govitecan, which was approved by the FDA in 2020 for the treatment of triple negative breast cancer. 36 Another type of multifunctional matchmaker modality that employs the induced proximity principle is the proteolysis targeting chimera (PROTAC), which is a hetero bifunctional molecule that downregulates target intracellular protein levels by utilizing the ubiquitin degradation pathway. 37 Arvinas is currently conducting clinical trials for PROTACs against various cancer targets 38 . Other potential future multifunctional modalities include a hormone that contains a combination of glucagon and thyroid hormone (Glucagon/T3) to treat various indications such as high LDL-cholesterol levels or improve glucose tolerance in rodent models of obesity. 39 Although these multifunctional modalities have not yet begun clinical trials, they are a good example of future fusion proteins that are on the horizon.

Manufacturing challenges associated with some of these multifunctional modalities will likely revolve around the lack of historical precedence. Because there is often no predicate molecule type that manufacturers will be able to emulate, critical quality attributes as well as the process controls necessary to produce a consistent product will need to be defined. In addition, novel assays will need to be developed that confirm the safety and efficacy of these products prior to regulatory approval.

The drug delivery system is critical to providing a safe and efficacious product to the patient. This section provides a brief overview of some promising drug delivery approaches which comprise liposome and nanoparticle technology for a targeted delivery, a coformulation approach for delivering more than one biologic in a single dose, non-invasive organ-targeted pulmonary drug delivery for biologics and 3D printing for solid dosage forms for a personalized medicine.

Liposomes are spherical, self-closed structures formed by a bilayer of amphipathic phospholipids with an internal aqueous cavity. The properties of liposomes can be characterized by size, number of lamellae, composition, ligand addition, and charge which all contribute to determine their stability in vivo and in vitro. Liposomal drug delivery systems are unique because they can be used for both lipophilic and lipophobic drugs. Liposomes display certain advantages such as biocompatibility and ability to carry large drug payloads such as DNA and RNA, and can be modified to better suit their pharmacological purposes. [40] [41] [42] An interesting example of a sterically stabilized liposome is ThermoDox ® , a heat-sensitive liposome which is currently approved for the treatment of hepatocellular carcinoma. 43, 44 Liposomes can further be modified by combining them with nanoparticles, which are a wide class of materials that include particulate substances. 45 Nanoscale-sized particles exhibit unique structural, chemical, mechanical, magnetic, electrical, and biological properties which can be utilized as delivery agents by encapsulating or attaching therapeutic drugs and delivering them to target tissues more precisely with a controlled release. VYXEOS ® , developed by Jazz Pharmaceuticals, represents a recent approval for a product utilizing liposomal nanoparticle drug delivery. It is a combination chemotherapy nanoparticle that encapsulates both cytarabine and daunorubicin to treat acute myeloid leukemia. It demonstrated improved efficacy at a lower dosage compared to free drug treatment, and also displayed an increased overall survival time in comparison to the control group. 46 Although the manufacturing of liposomal drug formulations has advanced significantly, there are considerable challenges that remain. Such challenges occur when nanoparticles and other ligands are used to alter molecular targeting, as these require the addition of more synthesis steps. Product quality is another important consideration as the manufacturing of liposomes can require multiple lipids, nanoparticles, and active pharmaceutical ingredients that may not be uniformly distributed. In addition, the manufacturing of nanoparticles typically requires the use of organic solvents, which can be difficult to completely remove from the final formulation. 

Biotherapeutics are parenterally administered typically either by intravenous (IV) or subcutaneous

routes. An IV administered dose is injected directly into the systemic circulation and can be adjusted according to patient weight, though it typically requires dose preparation and administration in a clinic and can be inconvenient from a patient-centric perspective. Subcutaneous administration has the flexibility of being delivered either in a clinic or self-administered. mAb therapies often require anywhere between 80 mg to 1000 mg per patient which translates to a concentration range of 150-200 mg/mL for the biologic. 48 High concentration mAbs injected subcutaneously must be transported to the lymphatic system before reaching systemic circulation. Dose retention in the subcutaneous space can be a limiting factor for bioavailability. Various factors including but not limited to the molecular weight, concentration of the biologic, viscosity, injection volume and the rate of clearance of the drug from the subcutaneous space govern the bioavailability of the drug product. 49 The maximum volume injection limit for a subcutaneous administration is much lower than other routes of administration and multiple doses may be required for solubility limited biologics. 50 Subcutaneous administration is often associated with pain due to drug product formulation properties (pH, buffer, viscosity and osmolality), administration technique (needle gauge, angle of injection), injection site and injection site reactions. 51 The ideal method of parenteral administration to maximize patient comfort would be a single-dose of an optimal formulation administered at the least J o u r n a l P r e -p r o o f painful site with the correct technique. ENHANZE ® is a novel drug delivery technology for subcutaneous administration using recombinant human hyaluronidase PH20 (rHuPH20). 52 Based on multiple clinical trials, rHuPH20 has shown promise in increasing injection volumes and increased bioavailability when compared to subcutaneous injections without rHuPH20. 53 55 Coformulated drugs represent a patient centric approach which increases patient comfort and compliance, reduce the cost of goods in manufacturing, and increases therapeutic yield. 56, 57 Coformulation is a fast-evolving space, but it poses significant biophysical and biochemical challenges for drug development when the formulation design space and administration regimes are different

Pulmonary delivery is an organ-targeted delivery which may improve the risk-benefit profile of certain therapeutics by delivering directly to the lungs. In fact, there are certain instances in which the therapeutic dose response is greater when compared to systemic delivery. A recent study has explored the potential of delivering a full length mAb for lung cancer in an animal model where a biologic was delivered using a digital inhaler. 58 The size of the biologic is an important factor, as full-length antibodies have low bioavailability and the smaller sizes of new modalities have the potential for better tissue penetration. A prerequisite for pulmonary drug delivery development is a generally recognized as safe (GRAS) formulation with optimal particle size for maximum deposition of the particles in the desired section of the lung. 59 Biologics are susceptible to various stresses and it is important to establish a stable formulation and in-process parameters that can ensure drug product as well as combination product stability for pulmonary delivery. The most common method of pulmonary drug delivery is with a nebulizer.

Jet, ultrasonic and mesh nebulizers are the three types of nebulizers currently available on the market. To achieve the optimal particle size and particle deposition in the desired area of the lung, it is critical to understand the aerodynamic properties of the nebulizer with the chosen modality. Factors such as viscosity, formulation, concentration of the biologic, excipients and concentration of excipients play an integral role in developing a stable pulmonary drug product 60 . Despite its challenges, pulmonary delivery has the potential to deliver biologics locally with minimal or no side effects as compared to systemic delivery for respiratory and oncology diseases.

J o u r n a l P r e -p r o o f 3.4

Conventionally pharmaceuticals are manufactured in large quantities, however manufacturers have recently explored options to reduce the manufacturing footprint of medicines. One emerging technology is 3D printing, which is currently limited to 3D printed devices, tablets, transdermal patches and vaginal delivery systems. 61 To date one 3D printed tablet, SPRITAM ® , has been approved by the FDA for the treatment of epilepsy. 62 3D printing has great potential to advance personalized medicine for patient-centric healthcare that enables customized doses for a specific patient population. In addition, 3D

printing has a smaller manufacturing footprint which may enable access to patient populations currently unreachable by conventional supply chains. However, 3D printing of drug products is still an emerging field and many questions remain to be answered regarding product quality attributes for a stable drug product. 3D printing may be the next big thing in personalized medicine, however a risk-based strategy based on prior knowledge and an understanding of the differences in manufacturing systems is still required before a safe and efficacious product can be made. 63 This technology has future potential applicability in the field of biologics.

This section primarily focuses on current regulatory CMC considerations from the US perspective. Advanced Therapies (CAT) providing specific expertise to aid in the assessment. Accelerated regulatory pathways of the EMA include the PRIME (PRIority MEdicines) scheme, conditional marketing authorization, accelerated assessment, or exceptional circumstances. It should be noted that most of the products that have obtained PRIME designation are ATMPs. 67 Once marketing approval has been obtained through the centralized procedure, it is valid in all European Union member states as well as

Iceland, Norway and Liechtenstein. Typical ATMPs include gene therapies, cell-based therapies, tissueengineered products, and combined ATMPs. Numerous guidance documents that are specific to each of these types of advanced modalities are available. [68] [69] [70] As evidenced by the previously described US and EU regulatory frameworks, novel biologics are supported by varying levels of published guidance or regulations, and sponsors are expected to meet all CMC requirements prior to regulatory approval. In general, manufacturers must provide enough data to demonstrate that their manufacturing process is adequately controlled to consistently ensure identity, purity, and potency of the final drug product. Determination of clinically relevant potency or a suitable surrogate can be a considerable issue for these novel modalities because traditional methods are typically not a reliable indication of clinical activity in a patient for the intended indication. Therefore, in lieu of a true potency assay, a more complicated functional assay that is more reflective of the mechanism of action may be required. However, the complexity of in vitro cell-based assays, which often use cell lines, can pose challenges in extrapolating relevant information for the in vivo clinical environment. In some cases, sponsors may explore validation of other endpoints that are indirect but relevant for potency, such as using vector copy number for a gene therapy. In these situations, sponsors should ensure sufficient data and documentation to support the alternative method in order to reduce the risk of rejection by regulatory agencies. Other important regulatory hurdles include the extensive characterization of the manufacturing process for these biologics, and both process parameter controls and critical quality attributes must be identified with strict statistical boundaries. Sponsors must also provide data demonstrating comparability of their products as the manufacturing process changes throughout the product lifecycle from clinical trial application to marketing application. Comparability determination can pose a considerable challenge during technology transfers, especially when the product is tailored to an individual as is the case with several of the newer novel modalities. Considering regulatory uncertainties for these novel modalities, health authorities often provide channels for early communication to facilitate industry/agency engagement. In the US, these can be both product-specific, with INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT), or non-specific, through the CDER Emerging Technology Team and the CBER Advanced Technologies Team. [71] [72] [73] In general, biologics must be characterized more extensively than small molecules for marketing approval to ensure safety and efficacy. For example, for a protein based therapeutic manufacturers must provide information such as the amino acid sequence, post-translational modifications e.g. glycosylation, disulfide bond configuration, and biological activity along with the appropriate documentation for cell J o u r n a l P r e -p r o o f growth and harvesting, details regarding the batch records, in-process controls, and process validation. 74 The FDA has recently issued draft guidance regarding the development of BsAbs. 75 In addition, the above-mentioned modalities such as CAR T cells or CRISPR fall under the category of gene therapy products, and there is currently drafted CMC guidance that contains applicable principles. However, one aspect that is reiterated in the information regarding the viral vectors to deliver the gene of interest is that the sponsor must provide detailed information regarding the components and process that were used to manufacture the vector. 66 The FDA has developed guidance documents for specific drug delivery considerations discussed available for conventional small molecules and well-characterized biologics from global regulatory agencies, the trend towards having modality-specific guidance for each new type of therapeutic on a regional basis will be difficult to sustain as the pace of guidance development inevitably will lag behind the inventive science and newer discoveries may be harder to classify under the existing knowledge base.

The resulting divergence in regulations will also add to the challenges in managing the drug development process. Individual regulator-sponsor discussions are resource-intensive and are not necessarily conducive to the overall goal of global harmonization and streamlined approvals. Guidance documents have also been provided in the field of drug delivery, where the innovation is focused on the delivery of patient-centric solutions to increase both patient comfort and compliance.

The birthplace of many of these innovations are academic labs or start-up entities that may not be well equipped to deal with either the commercialization of the technology or the associated regulatory hurdles when compared to established institutions or biopharmaceutical manufacturers. For innovative solutions, specific regulatory drug delivery guidance is often lacking and therefore there is an additional burden on the manufacturers to educate the agencies during this process. This lack of a clear regulatory pathway hinders the transition of a product utilizing a novel drug delivery mechanism to the clinical and commercial phases of development. There may be little clarity on how to assess the product's feasibility and manufacturability, and there often are additional quality requirements compared to conventional technologies such as those related to materials of construction as well as usability.

While accelerated regulatory pathways do exist, the clinical criteria and timing for these approvals tend to differ widely between countries. Work continues on other mechanisms to gain rapid approvals for and drive reliance practices through sharing scientific assessment reports for use in others' decisionmaking processes, and stresses that the ability to accept decisions made by trusted reference countries will support accelerated global rollout of approved critical products to achieve equitable access. 88 In addition, WHO recently released their "Good Reliance Practice" document in June 2020 focused on the use of work sharing, joint activities and recognition in order to avoid duplication of efforts. 89 Other lessons learned from the ongoing pandemic include the unprecedented speed of communication among the various groups collaborating across the globe in the race to develop therapies.

Guidance documents are also being published with greater rapidity than ever before, and these documents are valuable to understand the inherent flexibility that will be critical to regulatory assessment and approval. Communication with sponsors and ongoing dialogue will also look very different in the future, with more real-time information-sharing, involving perhaps even collaboration and not competition among different companies, regulators, medical professionals, and academic institutions. Not only have the industry and regulators partnered in the rapid development of suitable therapies, for example through the Emergency Use Authorization and Coronavirus Treatment Acceleration Pathway (CTAP) in the US, but through this partnership flexibility within the post-approval life-cycle management space is being leveraged to ensure manufacturing capacity for a potential COVID-19 therapy, once a treatment is available 90 .

Undoubtedly, during the pandemic the workload throughout the industry is immense, both from the viewpoint of regulators and sponsors. With the dramatic advancements in science being envisioned, there is a high probability that even after the pandemic subsides, the number of novel personalized therapies seeking approval will grow at a faster rate as sponsors look to restart development programs that were delayed by the coronavirus outbreak. 91 Thus, there is more acceptance now of innovative ideas J o u r n a l P r e -p r o o f including new applications of artificial intelligence and machine learning that have the potential to make disruptive progress in the efficiency and speed of drug development and totally change the paradigm for the future.

A Look into the Future -Recommendations from an Industry Perspective 5.

Though the challenges that lie ahead may appear daunting for the biotherapeutics industry and regulators, the opportunities for advancement are foreseeable and attainable. In the future, the manufacturing paradigm will change along with the regulatory landscape, as companies must now manage the expansion of therapeutic modalities from synthetics, therapeutic proteins and mAbs to include ever more complicated therapies, including live modalities. With this transition, product portfolios now often consist of over a dozen different modalities that require diverse manufacturing platforms.

Large batch fed production is likely no longer the optimal production model, specifically with low volume output, high diversity product portfolios. For these products, modular manufacturing models are more suitable as several products can be produced within a single facility at smaller scales providing the enhanced capability of switching manufacture more easily from one product to another in response to supply needs. For example, MIT researchers have already developed a benchtop system to rapidly manufacture biopharmaceuticals on demand which can be easily reconfigured to produce different drugs, enabling flexible switching between products. 92 The RNA "printers" being developed by CureVac and its collaborators would be able to make thousands of vaccine candidate doses at the point of use, for example in hospital pharmacies in individual countries around the globe. 93 As industry progresses towards personalized/precision therapies for smaller patient populations, we will likely see more and more utilization of modular facilities with turnkey construction/fabrication.

Additionally, due to varying regional regulatory requirements and the potential regulatory relief provided to in-country manufacturing, there may be more movement towards in-country, regional modular production.

Ultimately, companies will probably want to leverage a mix of manufacturing facilities from large fed-batch production to continuous modular production in order to optimize their manufacturing networks.

Manufacturers of the future will increasingly make use of automated networks and hardware that will improve the modular production process. This is because the automated networks will combine their collective computing power to monitor manufacturing and take the appropriate corrective and preventative actions to maintain the proper supply chains. These automated systems will also be capable of analyzing the quality of the drug product during manufacture to make sure that it remains within the appropriate statistical controls. By better harnessing the data available to us in an efficient and automated manner, and by leveraging modular manufacturing technologies we have an opportunity to deliver therapies to patients in an accelerated manner.

In addition to harmonization trends and acceleration options for products with great unmet medical need, the conventional regulatory assessment paradigm will also need to change drastically. In addition to understanding the intricacies of novel modalities and manufacturing technologies upon J o u r n a l P r e -p r o o f approval, there has to be a fundamental ability to adapt to the rapid improvement cycles for these new technologies and provide regulatory flexibility in order to keep up to date 94 . The regulatory paradigms could evolve to a real-time "learning" mode that utilizes the vast amount of data generated by the aforementioned automated systems instead of assessing every post-approval CMC change individually based on outdated platforms or data. Furthermore, regional post-approval life-cycle management activities must be harmonized and based upon science-and risk-based principles as outlined in ICH Q12. 95 Essentially, a global convergence of regulation provides an optimal setting for accelerated drug development, product life-cycle management and the advancement and acceptance of innovative technologies.

At the present time, there is acknowledgement that the pharmaceutical industry is not as "digitally mature" as many other industries; it is one of the least prepared and one of the most inefficient in leveraging the vast amounts of data available in an automated fashion. 96 In consideration of the fact that the volume of data generated in the biopharmaceutical industry will grow even faster in the future than it does today, innovative solutions for assembling, distributing and reviewing regulatory information are being considered. Structured content and data management (SCDM) solutions, in which data are collated into centrally organized content blocks for use across different documents, may aid in the efficient processing of data, creating opportunities for automation and machine learning in its interpretation. This technology will enable the industry to automate CMC content and data, drive changes in the agency review paradigms, improve filing preparation and review timelines, and enable real-time updates and data tracking. Thus, there is potential to truly drive harmonization of global regulatory filings and agency review processes including fostering connections with other sectors of the healthcare industry. 97 For instance, increasing this type of interconnectivity could allow for earlier detection of adverse events for marketed and experimental therapeutics or enhance biomarker and target discovery, but most importantly deliver life-altering therapeutics to patients at a faster pace and lower cost.

Applying CMC data and regulatory authoring automation concepts opens the possibilities to perform cloud based regulatory reviews, whereby a sponsor could upload structured Common Technical Document Module 3 content to a web-based cloud. The information uploaded to this cloud could be readily available to health authorities around the world in real time, thus essentially eliminating the common practice currently employed by biopharmaceutical regulatory departments of submitting filings to different regions in "waves". Thus, in a cloud-based system, an application would be submitted once, concurrently to all health authorities where a product registration is desired or if already commercially marketed, where a registration exists. Health authorities could benefit from a cloud-based application

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