Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Structured content and data management—enhancing acceleration in drug development through efficiency in data exchange

Structured content and data management—enhancing acceleration in drug development through... Innovation in pharmaceutical therapeutics is critical for the treatment of serious diseases with unmet medical need. To accelerate the approval of these innovative treatments, regulatory agencies throughout the world are increasingly adopting the use of expedited pathways and collaborative regulatory reviews. These pathways are primarily driven by promising clinical results but become challenging for Chemistry, Manufacturing, and Controls (CMC) information in regulatory submissions. Condensed and shifting timelines present constraints that require new approaches to the management of regulatory filings. This article emphasizes technological advances that have the potential to tackle the underlying inefficiencies in the regulatory filing eco-system. Structured content and data management (SCDM) is highlighted as a foundation for technologies that can ease the burden on both sponsors and regulators by streamlining data usage in regulatory submissions. Re-mapping of information technology infrastructure will improve the usability of data by moving away from document-based fil- ings towards electronic data libraries. Although the inefficiencies of the current regulatory filing eco-system are more evident for products that are filed using expedited pathways, it is envisioned that the more widespread adoption of SCDM, across standard filing and review processes, will improve overall efficiency and speed in the compilation and review of regulatory submissions. Keywords Regulatory science, Standards, Structure, Stability, Automation, Acceleration pathway, Chemistry manufacturing and controls, Structured content data management, Cloud-based systems processes are necessary in order to ensure product safety, Introduction efficacy, and quality, the staggered and prolonged time - The pharmaceutical industry is complex and highly regu - lines required for global approvals contribute to delays in lated, since global health authorities and biopharmaceuti- patient access to lifesaving medicines [1–3]. To expedite cal companies are mutually responsible for ensuring that product availability for indications with unmet medical marketed pharmaceutical products are safe and effica - need or serious illness, accelerated regulatory approval cious. While thorough regulatory review and approval pathways have been established in several different regions. *Correspondence: While these expedited regulatory pathways can result Jill Beierle in accelerated filings and, in some instances, faster naclhoh@gmail.com Department of Global Regulatory Affairs and Strategy – CMC, Amgen review/approval timelines, they require significant Inc, CA 91320 Thousand Oaks, USA resources, coordination, and program management for Department of Physiology, Johns Hopkins University School both regulators and sponsors. The use of these path - of Medicine, Baltimore, MD 21205, USA ways is often based on promising results from clinical © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Beierle et al. AAPS Open (2023) 9:11 Page 2 of 19 development but poses significant challenges for Chem - This article intends to highlight how SCDM and asso - istry, Manufacturing, and Controls (CMC) development ciated technologies can work synergistically with fast- and data in regulatory submissions [4–6]. For many tracked products to help address the regulatory CMC regions, the current regulatory process requires that challenges inherent in an accelerated development envi- CMC data be supplied primarily in Module 3 of the com- ronment. A summary of expedited regulatory pathways mon technical document (CTD) or electronic (e)CTD, and collaborative review processes is provided with dis- which consists of an XML backbone structure that pri- cussion on their specific challenges. Information on key marily houses PDF documents containing data, descrip- advancements in technologies that are supportive of tions, reports, and relevant certifications. The process of SCDM in regulatory submissions is also summarized. A compiling and maintaining CMC information and data in hypothetical case study, representative of a fictional filing document format requires substantial manual input and scenario, is presented to demonstrate how SCDM could rework throughout a product’s lifecycle, which is particu- potentially be applied to meet the challenges associated larly problematic for products undergoing accelerated with expedited product filings at various stages in devel - development with multiple simultaneous submissions at opment. Lastly, the future outlook is discussed. varying stages of development. Enhancing data manage- ment efficiency for regulatory submissions can help alle - Expedited regulatory pathways improve patient viate delays and reduce data entry errors by streamlining access to new medicines repetitive authoring tasks, structuring information to The decision to pursue an expedited review pathway allow for automation, and enabling data-driven submis- with a particular health authority is typically associated sion assembly and review [7]. with success in early-stage clinical development trials Towards this goal, the last few decades have fostered and demands earlier regulatory agency engagement in significant technological advancements within the phar - the development program as well as alignment on CMC maceutical industry, such as the International Society of considerations and filing expectations [15, 16]. Notably, Pharmaceutical Engineering (ISPE) Pharma 4.0 which novel modalities or therapies will need added collabora- includes incorporation of technologies including cloud tive discussions across quality, clinical, and non-clinical computing, big data analytics, Internet of Things (IoT), disciplines within health agencies. A barrier to speedy and artificial intelligence (AI), while supporting regula - access to new medicines for patients globally is the lack tory best practices [8–10]. While Pharma 4.0 encom- of harmonization in regulatory requirements, including passes a transformative model of manufacturing enabled those that impact accelerated filing pathways. Achieving by modern technology which complements Quality by an expedited approval designation in one country does Design (QbD) principles [11], in general, the pharma- not guarantee that it will be granted elsewhere [17]. A ceutical industry has been slow to adopt the necessary summary of accelerated review pathways in several major technological advancements in information systems that markets is presented below. enable modernization of information exchange and data The need to accelerate the availability of new therapeu - management. Structured content and data management tics was enacted in the United States (US) in 1988 by the (SCDM), which allows information to be modularized Food and Drug Administration (FDA) with interim regu- and reused across a centrally managed content reposi- latory procedures intended to expedite the development tory, has emerged as a tool which provides a potential and review of new drugs to address unmet medical needs solution to target many of the efficiency challenges for in treating serious or life-threatening conditions (21 CFR CMC documents that persist during regulatory submis- 312) [18]. Since then, the FDA has adopted five programs: sion and review processes [7, 12]. While there is pres- Fast Track Designation, Breakthrough Therapy Designa - ently an abundance of cautionary thinking within the tion (BTD), Accelerated Approval, Priority Review, and pharmaceutical and biopharmaceutical industry with Regenerative Medicine Advanced Therapy (RMAT) [19]. regard to investment in novel information manage- Both BTD and RMAT are intended for drugs treating ment technologies, the value of SCDM and Pharma 4.0 serious or life-threatening illnesses and provide spon- enabling approaches will continue to increase as digital sors with similar advantages, with BTD regulated by industrialization continues and demonstrates the utility the Center for Drug Evaluation and Research (CDER) of rapid information sharing as a tool for increasing effi - and RMAT by the Center for Biologics Evaluation and ciency in regulatory submissions [13, 14]. Additionally, Research (CBER). In 2021, CBER approved three thera- resistance to leverage twenty-first century technologies peutics with the RMAT designation pathway and CDER hinges on our industry being highly regulated. However, approved 14 through BTD [20, 21]. the banking industry is also highly regulated, yet most In 2018, the FDA’s Oncology Center of Excellence global monetary transactions utilize similar technologies. (OCE) initiated Real-Time Oncology Review (RTOR) to B eierle et al. AAPS Open (2023) 9:11 Page 3 of 19 streamline the review process and further facilitate the treats a serious disease and/or shows clinical usefulness availability of groundbreaking therapeutics to patients by meeting an unmet medical need or shows improved with life-threatening conditions [22, 23]. With RTOR, efficacy and safety compared to current options. Condi - the sponsor and regulators carefully plan and agree tional early approval (CEA) applies to drugs where it is on a strategy and timeline for the rolling submission of difficult to provide confirmatory trials or doing so would module components. Although the Prescription Drug be too time consuming and the MA can be filed with User Fee Act (PDUFA) review clock does not officially adequate levels of efficacy and safety during exploratory begin until the last document is submitted, by supplying trials. Confirmatory clinical trial data must be submit - selected sections earlier, applications can sometimes be ted post-approval. The Sakigake designation is aimed at approved 3 to 4 months before the PDUFA goal date [24]. drug products targeting unmet medical needs, or for the The European Medicines Agency (EMA) has also treatment of serious or life-threatening conditions, and implemented several regulatory procedures designed to pairs the sponsor with a PMDA staff review concierge to expedite patient access to new medicines, including Con- streamline communication throughout the development ditional Marketing Authorization (CMA), Exceptional and application process. Sponsors also benefit from roll - Circumstances for rare diseases, Accelerated Assess- ing reviews, a shortened review period, and the ability to ment, Priority Medicines (PRIME) and Compassionate provide submission materials in English. During the first Use [25–29]. A common feature for eligibility for these 5 years, 37 drugs received this designation, and 10 were pathways is an “unmet medical need.” Certain pathways approved [35, 36]. like CMA also apply to orphan drug medicines which Several international collaborative review initiatives treat rare diseases (defined as those with a prevalence across regulatory agencies have been initiated to allow of 5 in 10,000 or less). However, the understanding of faster patient access to critical medicines, globally. Pro- “unmet medical need” in the EU, where there is no formal ject Orbis and the Access Consortium are two exam- definition, is very different from that laid out by the FDA ples of collaboration amongst regulators that have been [30]. Most of these pathways allow for the deferred sub- operating for several years. Project Orbis was initiated mission of certain information as post-approval commit- in May 2019 by the FDA’s OCE to leverage the scientific ments such as phase III clinical data, long-term stability and regulatory knowledge across participating countries data, and other data to refine the product manufacturing to enable faster global access to crucial cancer treatments control strategy. Each pathway follows its own timeframe [22, 37]. Review efficiency is improved through resource and expedites the review and approval to varying extents. sharing (e.g., by sharing reviews between the participat- Of the available expedited approval pathways, only CMA ing regulatory agencies). As of August 2022, eight coun- and PRIME are potential options outside the scope of an tries take part in Project Orbis: Australia, Brazil, Canada, emergency. In 2021, the EMA approved 13 drugs with Israel, Singapore, Switzerland, the United Kingdom (UK) CMA and six with PRIME designation [31]. and the US. In 2021, the FDA approved 26 marketing During the COVID-19 public health emergency, the applications supported by Project Orbis [38]. The Access heightened need for vaccines and/or therapies resulted Consortium, established in 2007, is a collaborative effort in the EMA allowing for a “rolling review” mechanism between regulatory agencies in Australia, Canada, Sin- under the “EMA plan for emerging health threats” [32, gapore, Switzerland, and the UK, that would benefit 33]. With this review mechanism, the EMA and the from work-sharing, enhancing synergy, and increased sponsors preemptively agree to a series of rolling reviews efficiency by reducing duplication [39, 40]. In addition, with predefined document submission timelines. This sponsors have the advantage of receiving consolidated allows documents to be submitted and reviewed as data questions from multiple markets, predictable timelines become available. Once the application package is con- for information requests (IR), and potentially, near- sidered sufficiently complete, the sponsor can proceed to simultaneous approvals in multiple markets. apply for CMA. As with other CMAs, additional data can The International Coalition of Medicines Regulatory be submitted post-approval. This process enabled a faster Authorities (ICMRA) is a voluntary organization com- review of COVID-19 vaccines to meet the public health prised of 24 member regulatory agencies and 15 associate emergency. member agencies. Together, they work to identify areas of Japan’s Pharmaceutical and Medical Device Agency potential synergies and leverage existing resources when- (PMDA) has three main pathways available for expedited ever possible [41]. At the start of the COVID-19 pan- review of a marketing application (MA): priority review, demic, the ICMRA issued a statement of collaboration. conditional early approval, and Sakigake [34]. Prior- This led to a large regulator-industry workshop in July ity review shortens the review time from 12 months to 2021 which was well-attended and had broad outreach 9 months. The criteria for this pathway are that the drug [42, 43]. From these discussions, the framework for two Beierle et al. AAPS Open (2023) 9:11 Page 4 of 19 collaborative pilot programs was developed: one for facil- of multiple presentations at risk and may require ity inspections, and the other for the assessment of CMC additional clinical stage amendments to support the post-approval changes. The two pilot programs began selected presentation intended for commercializa- accepting applications in June 2022 and are both under tion. Furthermore, the transition to commercialization oversight by the ICMRA working group for pharmaceuti- may include changes to the manufacturing site and/or cal quality knowledge management systems [39, 44]. The scale to meet projected demand for the product, which primary goal is to explore the feasibility of collaboration in part explains why data to support process valida- for facility inspections and increased harmonization of tion and product stability are on the critical path for data expectations for CMC post-approval submissions, the target submission date. These effects of accelera- both efforts that can be supported by improved manag - tion can result in limited commercial product supply ing of source data. at time of product launch onto the market, increasing the complexity of the CMC strategy and the number of CMC challenges in regulatory submissions post-approval changes, and thereby increased regula- of products under accelerated development tory submissions. Clearly, management of accelerated Based on a benefit-risk assessment, many acceler- global filings is complex and requires careful track- ated procedures outlined in the previous section allow ing of various data requirements which increase as a phase 2 data that shows clear indication of efficacy product progresses through development, expands to to be used as the pivotal clinical data for submission include submissions in multiple countries, and man- with phase 3 confirmatory studies to be started dur- ages responses to health authority questions along ing the MA review cycle for completion post-approval with post-approval changes and commitments (Fig. 1). [45]. However, accelerated clinical development poses This is a highly resource-intensive process that can major product development challenges by compress- be protracted for some years and is further delayed ing essential CMC activities into shortened clinical by reliance on archaic filing mechanics to relay CMC timelines, thereby potentially placing the required data. Therefore, efficiency gains in the processes that CMC data on the critical path for marketing authori- govern a filing strategy are of critical importance. zation submission [4–6, 46]. Optimal dose selection is These complexities in managing the submission often pending at the time of first subject dosing in crit- planning can be addressed in part by robust yet flex- ical registrational trials. This forces the development ible knowledge management which may be afforded Fig. 1 Compounding submission volume and complexity during development. The quantity of dossiers, country variants, information requests, and manufacturing changes substantially increases over time. For accelerated programs, later stages of development are often characterized by overlapping milestones and filing expectations, wherein the phase 3 trial may overlap with the filing of the marketing application. The marketing application may be filed in multiple discrete “waves” including groupings of different regions, wherein authoring, review, and approval timelines may overlap B eierle et al. AAPS Open (2023) 9:11 Page 5 of 19 by SCDM that works directly with content and data Current applications of SCDM rather than documents. Ultimately, in the current non- in the pharmaceutical industry digital document-based submission paradigm, incor- In addition to targeted CMC acceleration tools and poration of critical CMC data into the filing requires expedited regulatory pathways, Information Technology significant time and resources for authoring, data veri- (IT) infrastructure can be effectively leveraged to man - fication, formatting, and publishing, all of which nega- age resource demands and complex filing scenarios for tively compete with the expedited clinical timeline. To industry and global health authorities. While individual minimize the timeframe for preparation of CMC infor- organizations may pursue a multi-pronged approach to mation, innovative approaches and tools are needed IT modernization that consists of various elements of that facilitate efficient management of CMC data in Pharma 4.0, such as AI and machine learning, SCDM regulatory submissions. is of particular importance for enhancing data manage- Health authorities and industry pharmaceutical trade ment capabilities to support regulatory filings. SCDM is a organizations have recently discussed tools to support component-based approach to information management CMC acceleration. Along with existing submission that can drive regulatory modernization and provide strategies such as rolling reviews and negotiations on solutions for efficiency challenges faced by sponsors and uses of the established term “prior knowledge,” several regulators. SCDM can incorporate structured and semi- new ideas were introduced and considered during the structured data, wherein structured data is largely tabular COVID-19 emergency and may potentially be carried and in a highly ordered sequence which typically ascribes over to expedite product development outside of emer- to a controlled terminology list. Semi-structured data gency circumstances. Under PRIME, the EMA released retains a partial hierarchal format but allows for flexibil - a valuable toolbox for CMC acceleration that was avail- ity through input of free text.  Conversely, unstructured able in a draft form through 2021 and was published data is free text that contains terms that provide essential in 2022 [47]. Likewise, FDA released a new Manual information, typically in paragraph format (Fig. 2). of Policies and Procedures (MAPP) titled “Quality SCDM is based on the concept of a centralized and Assessment for Products in Expedited Programs” and interoperable data repository or library that is comprised plans to start the CMC Development and Readiness of modular content authoring blocks and data elements Pilot (CDRP) in 2023 to accelerate CMC development that build upon each other to create a product-specific for Investigational New Drug (IND) sponsors at both record. Using this concept, a content block can be defined CBER and CDER [48–50]. as a container for a stack of data elements, wherein the In addition to the regulatory tools and strategic data elements relate to one another and commonly methodologies described above, utilization of technol- appear together to comprise a data set or description of ogy to streamline the data management, authoring, a specific attribute (Fig.  3). SCDM leverages the reusabil- and verification of CMC information presents a com - ity of content from a given content block to build related prehensive approach for alleviating the impact of pre- content blocks or to facilitate reuse of the same content sent acceleration challenges. Capabilities  like SCDM block across applications, thereby drastically limiting the provide enhanced functionality in comparison to con- need for consecutive authoring, reviewing, and approval ventional submission preparation processes, aiming to cycles of the same content block or data element [7]. Data improve efficiency while simultaneously promoting a elements or content blocks can be distributed across science and risk-based assessment by reducing the time multiple electronic common technical document (eCTD) between digital data generation and data availability in sections for various regulatory filing requirements and the filing for health authority review [46]. SCDM could can be efficiently updated throughout the product lifecy - also support optimization of reviewing procedures cle. This interoperability can ease the burden of repetitive for health authorities through sharing of information authoring and allow for the auto-population of content, across applications or through a cloud-based system. which can be updated in real-time as changes or new Above all, the value of SCDM would be most evident data are applied. The narrative can be refreshed accord - for sponsors simultaneously managing multiple expe- ingly with author input as necessary. Eliminating data dited submissions worldwide, with responses to health verification alone with the use of a validated SCDM sys - authority questions and subsequent post-approval vari- tem significantly reduces review time and resources, as ations needed to optimize the manufacturing process there is no manual data transcription. As module 3 of over time [4–6]. The ability to repurpose prior knowl - the eCTD is comprised of designated datasets and ref- edge and other product filing data libraries rapidly for erenced details that are repeated across multiple nodes numerous submissions would provide an enormous (or CTD sections) in an unstructured format, regulatory gain in efficiency [47, 51–53]. dossiers become increasingly cumbersome to maintain Beierle et al. AAPS Open (2023) 9:11 Page 6 of 19 Fig. 2 Data formatting conventions for regulatory information. Sample stability data illustrating unstructured, semi-structured, and structured data formats are depicted. Key content and data input fields are highlighted in gray for visualization. While unstructured data characterizes much of the current format, SCDM principles are optimally applied to semi-structured or structured data. While data appearing in a structured table appears simplified, the raw data is still accessible via a variety of viewing formats. While not inclusive of all possible interfaces and navigation options, an example shown here utilizes “hover text” that shows the corresponding data value when the “conforms to criteria” field is highlighted Fig. 3 Structured content and data library for stability data. An overview of a structured content and data library housing stability information is depicted. Each black box constitutes a “content block” that is attributed to a specific lot. Inside each content block, information such as test method, acceptance criteria, and timepoints are accessible. Data is imported into the library directly from the data source (ex. LIMS, eLN). Over time, as development progresses, stability data continually accumulates across lots and, additionally, new lots are developed as the manufacturing process is optimized. Content blocks data elements are updated in real time as new data points become available from data sources. Content blocks and data elements can be “pulled” from the library to auto-populate module 3 CTD sections to prepare for submission B eierle et al. AAPS Open (2023) 9:11 Page 7 of 19 and continually update, particularly in the post-approval Similarly, SCDM can bring data from multiple man- environment wherein there can be multiple variations or agement systems together and allow for data intercon- supplements in preparation simultaneously. With SCDM, nectivity across systems through integrations. Currently, the individual content blocks can be structured, mapped data are stored and managed across multiple internal to different eCTD nodes where they are needed, and systems, such as Laboratory Information Management linked to a centralized data element repository for stor- Systems (LIMS), Electronic Lab Notebooks (eLN), Prod- age and maintenance, enabling an easier authoring pro- uct Lifecycle Management (PLM) software, and company cess and enhancing automation [12]. Instead of editing, data lakes. This makes it difficult to transfer, assimilate, data verifying, and republishing a full document, modifi - and track source data in preparation for regulatory sub- cations can be made to individual components as needed, missions. SCDM can be leveraged to build connectivity which will then auto-update in each section in which the between systems by structuring and contextualizing con- components appear. In this way, changes can be applied tent. The structured content and data library can ulti - across multiple sections and multiple regions simulta- mately be used in combination with an enterprise data neously. From a technical perspective, SCDM can facili- lake (EDL) to achieve a unified CMC data model that tate parallel review activities across different agencies establishes semantic context between data elements and by helping to manage multiple country-specific varia - is fully interoperable across systems and applications tions that impact the same CTD section, such as speci- [12]. fication sections, which may be different across regions The use of SCDM in a regulatory and pharmaceuti - due to individual agency regulatory requirements and cal context is in its relative infancy with comparatively preferences. An additional compelling advantage to hav- little real-world experience versus traditional operat- ing such a centralized data repository is to support the ing models for submission assembly. Biopharmaceuti- acquisition and integration of a program/company, where cal companies, as well as global health authorities, have the new sponsor company is responsible for retrieving begun to preliminarily explore SCDM-based architec- archived data to support new submissions at various ture and solutions internally within recent years as part points in the product lifecycle, often in the absence of the of a larger shift towards regulatory modernization and technical development experts. digital system expansion, but it is not yet a widespread In addition to supporting efficiency by optimizing industry standard or regulatory expectation [7]. Several how content is authored, managed, and reused, SCDM other industries with their own sets of complex regula- can also enable digitalization by decoupling CMC data tions have demonstrated successful use cases digitization, from discrete documents, to move towards a data-driven including banking and financial services, the food and approach. As discussed previously, structured content beverage industry, automotive industry, marketing, and using a re-usable structured content and data library can aerospace, which showcases the suitability of structured house modular blocks of information (data with meta- content across complex, regulated environments [56–61]. data tags) to be used internally to build the content of There is increasing support towards implement - an on-demand internal data report, as well as externally ing structured content-based solutions in life sciences to address a health agency data request [12, 54]. For and pharmaceutical organizations which is demon- example, in FDA submissions, a drug master file (DMF) strated, in part, by the emergence of commercial tools is a current mechanism for reusing data, which can be offered by software and data management support ven - replaced with SCDM for future applications. This “data dors for SCDM solutions tailored for biopharmaceuti- on demand” SCDM approach can be considered a tech- cal use cases. Over the past 5 years, as companies have nologically advanced version of the DMF mechanism. adopted SCDM approaches internally, technological The DMF can be updated and maintained routinely in solution developers have evolved alongside the industry, an automated manner independently from a given filing as many vendors now showcase customer testimonials or application. For example, stability data stored in the and successful case studies from across multiple domains cloud for different drug product CTDs can be directly of biopharmaceutical companies, including research pulled for a new submission using SCDM. In a similar and development, regulatory, labeling, and operations. manner as using data from the DMF, SCDM can share Select examples of platform-based applications devel- submissions and data in a digital format in the cloud. oped to support the management of CMC regulatory Easy digital access to data used in amendments, varia- data include Docuvera’s CMC solution, which provides tions, annual reports, and supplements can be repur- a single-source authoring system for reviewing, approv- posed in specific areas of a submission for use globally ing, publishing, reusing, and managing CMC content; ® ™ depending on agency requests [55]. Cognition’s Lighthouse system, which can generate automated structured stability data reports from data Beierle et al. AAPS Open (2023) 9:11 Page 8 of 19 imported manually or from source systems of record; content and structural requirements, they lack the level and QbDVision , which has a suite of content manage- of section-by-section detail and granularity that would ment solutions for organizing and reusing CMC data be needed to support a fully structured application. The throughout the product lifecycle [62–64].  Other solu- lack of data standardization leads to the increasing het- ® ® ™ tion providers, such as Cognizant, IQVIA, OpenText , erogeneity of submissions across sponsors and regula- Esko, InteliNotion, and Vasont , have created SCDM tors, as sponsors may submit data in multiple formats tools specifically for life science and biopharmaceutical while regulators at different agencies may use different information management, which can be applied across tools and metrics for assessment. Differences in syntax domains, including CMC [56–59]. Vendors such as Veeva and nomenclature can make it difficult to map pieces of and LORENZ are creating specific toolsets to help organ - information that are conceptually identical. For exam- ize structured data in line with upcoming regulatory ple, the pharmaceutical dosage form categories “cap- data requirements [65, 66]. Additionally, companies may sule, hard” and “hard capsule” are definitionally the same develop in-house applications using commercially avail- and ontologically should be modeled as the same object able data visualization programming packages (e.g., R (thing). Similarly, a release specification result for a criti - Shiny) that are specifically customized to integrate with cal quality attribute may be operationally identical to the existing business data architecture and deliver structured stability time zero result for that attribute and should be content solutions [67]. The availability of configurable modeled for both purposes. However, if this mapping is commercial software and Software as a Service (SaaS) not properly conducted or completed, these items could platform solutions increases the accessibility of SCDM be rendered as separate objects and create limitations for wider implementation across biopharmaceutical for machine-based assessment and content auto-popula- companies with differing organizational sizes, technolog - tion. Ultimately, these differences in terminology across ical capabilities, and data complexity. regions create unneeded complexity that contributes to variations in data interpretation. Emerging regulatory enablers of SCDM The International Organization for Standardization While adoption of SCDM solutions can support effi - (ISO) originally published the Identification of Medici - ciency and optimization of resource management, par- nal Product (IDMP) standards in 2012 with the objec- ticularly in accelerated filing scenarios, there is presently tive of enabling simplicity and consistency of medicinal no requirement, or significant external impetus, for biop - product and substance data that are exchanged between harmaceutical developers to pursue these advancements sponsors and regulators [68]. IDMP standards span mul- in technology as dossiers can be compiled and organized tiple different domains in the pharmaceutical industry manually using current operating procedures. However, in a limited scope, including product labeling, safety, as the industry collectively advances towards digital pharmacovigilance, and CMC, focusing on the elements maturity as part of Pharma 4.0, the need to reconfigure that are deemed most essential for medicinal product from unstructured to structured data management solu- and substance identification. Specific coverage areas tions will be further escalated by key imminent develop- include product and substance nomenclature, manufac- ments that are gaining momentum globally with several turers, characteristics, marketing authorization status, health authorities. and packaging details. Several regulators, including the EMA, have communicated their intentions to require Emerging submission requirements for structured, compliance with ISO IDMP standards, but formal guid- standardized CMC and quality data ance towards implementation is pending across multiple Data standardization is a key driver for automation and regions. represents an important step towards structuring data by Specifically, the EMA plans to implement ISO/IDMP enabling consistency and interoperability. Presently, there compliance by utilizing an approach based on the four are no data standardization requirements for CMC data domains of data within pharmaceutical regulatory pro- that are submitted to regulatory authorities. While spon- cesses including Substance, Product, Organization and sors must meet the requirements outlined in local leg- Referentials (SPOR). EMA’s efforts intend to facilitate islation and are advised to follow relevant International the reliable exchange of key medicinal product infor- Council for Harmonization of Technical Requirements mation in a structured, standardized, consistent, and for Pharmaceuticals for Human Use (ICH) guidance and efficient manner in line with the healthcare industry regional and country-level guidance, there are no data [69]. While the implementation timeline for SPOR standards currently in use that govern how data are pre- is to be determined, the EMA is expected to initiate sented, formatted, and structured in the regulatory dos- the implementation of IDMP standards through the sier. Although ICH M4Q guidelines provide baseline related Digital Application Dataset Integration (DADI) B eierle et al. AAPS Open (2023) 9:11 Page 9 of 19 Adoption of data analytics tools to support regulatory project, which will replace the current PDF-based review electronic Application Form (eAF) with a web-enabled In 2018, the FDA first shared its plans to create a risk- form [70]. based, computer-aided reviewing tool entitled Knowl- Separate from SPOR, the FDA has developed an edge-Aided Assessment and Structured Application alternative data standardization initiative, focus- (KASA) [81]. The KASA tool would input received struc - ing specifically on CMC data requirements under tured data into an analytical database that utilizes risk the Pharmaceutical Quality/Chemistry, Manufactur- assessment algorithms to evaluate key CMC and quality ing, and Controls (PQ/CMC) project that expands attributes, such as manufacturing facilities, pharmaceu- the IDMP concept across CMC. The initiative aims to tical development, and control strategy [82]. The KASA enable sponsors to pivot toward providing structured tool is intended to address inefficiencies in the review data applications to improve interoperability between process, promote consistency and objectivity during stakeholders and increase the efficiency of the FDA’s analysis, and keep pace with technological innovation in review of CMC data. As part of the 2012 Food and Drug line with the goals of the Pharmaceutical Quality for the Administration Safety and Innovation Act (FDASIA), 21st Century Initiative [76]. The FDA’s related PQ/CMC the FDA released an initial Federal Register Notice in initiative would support implementation of KASA by 2017 on a series of structured data elements intended enabling sponsors to provide structured data in an appro- to provide structure across a variety of CTD mod- priate format at the time of regulatory submission, which ule 3 sections, including stability, specification, ana - could then be directly imported into the KASA tool for lytical methods, and batch analyses [71]. In 2022, the analysis. Both initiatives represent a change in thinking FDA shared a refined and expanded version of the PQ/ towards an objective data-driven, risk-based decision- CMC data elements including mapping to Health Level making approach wherein unstructured narrative is 7 (HL7) Fast Healthcare Interoperability Resources minimized in favor of usable, assessment-ready data. The (FHIR) [72, 73]. initial scope to pilot the KASA tool included Abbreviated The FDA’s PQ/CMC standards as well as the EMA’s New Drug Applications (ANDA) for generic drugs, as SPOR rely on exchange specifications to enable the this represents both a high-volume area for FDA review- transfer of information from sponsors to health author- ers and a high-impact area for consumers. The solution ities. Both standards utilize FHIR as an exchange stand- is anticipated to evolve over the next 5 years to include ard. HL7 FHIR is an open-source data format with an a review of New Drug Applications (NDAs), Biologics accompanying application programming interface License Applications (BLAs), and post-approval changes (API) that leverages flexible and modifiable resource [76–79]. elements to bring structure and standardization to healthcare information while allowing for targeted cus- Innovations in cloud‑based technology tomization [74]. Through FHIR, sponsors and health Cloud-based computing harnesses the collective power authorities will be able to securely exchange elec- of numerous interconnected servers to enable a custom- tronic correspondence through FHIR messages, which izable suite of computing and processing capabilities, can include a bundle of structured information that is including analytical tools, software applications, remote downloadable in a variety of formats including XML data storage, and access to volumes of information on- and JSON. FHIR can accommodate regional variations demand via the intranet/internet. Flexibility, scalability, in terminology lists, which supports its use as a flexible, and interoperability are among the key value propositions global solution for standardization [75–79]. for cloud services, which allow systems within the cloud- In addition to FDA’s and EMA’s efforts to develop based ecosystem to communicate with one another, FHIR-compliant data standards, a new HL7 FHIR pro- bringing data from different sources together to achieve ject was established in late 2022 with the goal of devel- new levels of accessibility. For pharmaceutical companies oping global internal data standards to enable exchange and regulators, the practicality of SCDM can be further of data across biopharmaceutical industry data systems. augmented by a cloud-enabled unified data model that These standards are being developed in collaboration connects data to allow for the seamless access and use of with industry stakeholders and will maintain alignment data [12]. with both PQ/CMC and ISO IDMP to the extent fea- Regulators are increasingly moving towards cloud- sible. The project, entitled, “Data Exchange Industry – based systems to optimize processes such as data Pharmaceutical Quality (dx-PQ)” will cover a variety of exchange, assessment, and archiving. In the US, as scenarios in its initial iteration, including technology part of the FDA’s Technology Modernization Action transfers, manufacturing process changes, and stability Plan (TMAP), the agency is exploring next steps and data updates [80]. Beierle et al. AAPS Open (2023) 9:11 Page 10 of 19 requirements for migrating the FDA’s IT infrastruc- secure workspaces that will be made broadly accessi- ture to a cloud-enabled model. As reported in the 2022 ble by all life science companies and health authorities TMAP Anniversary Report, 35% of the agency’s systems around the globe. The long-term vision of the platform is are utilizing cloud-based approaches, which has contrib- to decrease regulatory submission and review timelines, uted to significant resource savings and assisted with the as well as development costs, to accelerate availability of development of scalable next-generation data centers medicines for patients. As an integral aspect of the vision [83]. Similarly, in the EU, the EMA has shared its intent to establish a cloud-based data exchange platform, the to migrate its IT systems entirely to the cloud by 2025 Accumulus platform aims to support and aid adoption to allow the agency to further modernize and digitize its of the aforementioned CMC data standards currently in operations [84]. To date, many of the externally facing development through a flexible and accessible user inter - systems used by the EMA have already adopted a cloud- face and structured data repository. Notably, Accumu- enabled infrastructure, such as the EMA’s IRIS platform, lus Synergy is a primary stakeholder in the development which can be utilized to initiate a number of regulatory of the HL7 industry internal CMC data standard, Data procedures such as applying for orphan drug designation, Exchange Industry – Pharmaceutical Quality (dx-PQ) seeking scientific advice, and providing updates on mar - [80]. keting authorization status for products [44, 85]. While it is important for regulators to upgrade and Applying the principles of SCDM modernize their own internal systems to promote con- through the product lifecycle regulatory process: tinuous technological innovation and advancement, a case study regulators and sponsor companies would benefit from In this section, a hypothetical case study is presented as having a common, international, cloud-based informa- an example of how SCDM can be leveraged to increase tion exchange platform to conduct correspondence and efficiency in CMC submissions for a medicinal product initiate regulatory procedures. In 2020, Accumulus Syn- in an accelerated development scenario. Figure  4 illus- ergy, a nonprofit organization and technical solution trates the high-level development timeline demonstrating innovator, was formed in response to this growing need. this example product. Early MA submissions (“wave 1”) Accumulus Synergy is creating a cloud-enabled solution are planned on the basis of compelling phase 2 clinical that fosters collaboration between and across regula- data. As a result, the clinical trial application (CTA) sub- tors and industry, enables real-time regulatory submis- missions supporting confirmatory phase 3 studies may sion, and allows for dynamic structured data exchange be ongoing at the same time, resulting in overlapping for CMC and other domains [86]. With support from workload and adding to project management challenges. 12 biopharmaceutical sponsors, Accumulus is develop- The timing of necessary changes to the manufacturing ing a scalable, democratized platform with shared and process, product formulation, strength, and container Fig. 4 Case study summary timeline. The timeline outlines the major regulatory filing milestones for the hypothetical case study. Each filing activity milestone is able to leverage substantial content and data reuse supported by the structured content and data library to streamline authoring and submission B eierle et al. AAPS Open (2023) 9:11 Page 11 of 19 closure system or site must be carefully considered in to the overall program timeline. SCDM better supports order to ensure uninterrupted supply to patients glob- incorporation of any CMC updates that are needed dur- ally. Due to the compressed timelines, certain elements of ing this delay since these are captured within the content product optimization as well as many necessary changes library via content blocks and data elements. These ele - may need to be deferred to the post-approval stage, at the ments can be readily deployed to relevant parts of the same time as filing of the “wave 2” MAs. regulatory applications concurrently for all countries. The product is identified in pre-clinical development The advantage of SCDM in this scenario is agility through as a potential target for undergoing accelerated develop- rapid incorporation of updated CMC information in sub- ment. Leveraging SCDM technologies, discovery, and missions, in response to clinical timeline changes as they preclinical data are appropriately logged and catego- occur in real-time. rized in a cloud-based EDL and structured content and When compelling phase 2 clinical results are received, data library where data are centrally stored, organized, applications are made to gain expedited regulatory path- and made accessible for future component content use. way designations (BTD in the US, PRIME designation Before first-in-human (FIH) studies can take place, the in the EU, and Sakigake in Japan). Further complexities regulatory team initiates the process of drafting CTAs to are evident if an expedited review designation is received support initial studies, focusing on inaugural target mar- in one market and not in others, resulting in staggered kets. The team accesses the data content from pre-clini - submission planning and constantly shifting scenarios. cal studies in the EDL and structured content library to Unanticipated early approvals also may necessitate accel- map relevant component content blocks to each respec- eration of scale-up and site transfer activities to meet tive CTA filing. This process enables a direct digital con - ongoing clinical trial supply demand and commercial nection between material used in preclinical and early requirements for each of the multiple countries targeted clinical studies, which has historically been challenging for wave 1 MA submissions. The team is also simultane - as it spans many years and personnel changes. Continual ously managing CTA submissions for multiple confirma - data collection from these early process development tory phase 3 clinical trials to support additional data experiments is enabled by tagging and mapping informa- collection across regions. As shown in Fig.  1, this repre- tion that can populate product and region-specific con - sents an intense period of overlapping submissions and tent blocks in a data library. These content blocks contain responses to health authority requests for information for all the CMC information that can be built sequentially both CTAs and MAs. Participation in collaborative regu- as the product development program matures, as shown latory efforts such as Project Orbis requires further coor - in Fig.  3. Following any required updates due to agency dination and handling of multiple simultaneous requests questions from the initial CTA applications, content for information, often with short turnaround times as blocks can be re-used for streamlined file-building and well as country-specific CMC summaries such as quality submission operations in subsequent CTA filings, in assessment aids required by regulators. line with the global regulatory strategy. As opposed to Without SCDM, the MAs would be prepared follow- authoring documents specific to each filing, the product ing current practices, in which a core CMC dossier is first data are accessible and reusable via a multi-dimensional created from data sources with aggregate information data network of semantically connected data elements requirements for all countries. From this global dossier, throughout the product lifecycle. In lieu of tracking down the team would need to prepare multiple country-spe- and aligning documents with specific phases of develop - cific MAs and ongoing CTAs. Since this team does have ment and regions, data elements of the content record an established SCDM workflow, they do not need to can be flexibly deployed to the required filings from a manually generate the different documents and variants. core content repository. This agility is especially valuable The tagged data in the content block is retrieved from given the shifting timelines that are often associated with the EDL and structured content library and loaded into accelerated development. the relevant sections of the application. Thus, data can As clinical studies progress, alignment between the travel from a centralized EDL that is comprised of a con- clinical and CMC activities must be continually evaluated solidation layer (that accrues relevant product data from and maintained, as changes to clinical development mile- various data sources) and a semantic layer (that connects stones may substantially impact CMC resource alloca- the product data elements based on an ontological data tion and timelines. For example, if late-breaking clinical model which defines the relationships, classifications, results were to suggest that the product delivers substan- and associations of data elements in a cloud-based eco- tial benefit in a subset of the patient population with a system) (Fig. 5). specific genetic mutation, development of a companion Most of the health authorities in this hypothetical diagnostic would be required which might cause delays case study accept MA submissions in eCTD format, but Beierle et al. AAPS Open (2023) 9:11 Page 12 of 19 Fig. 5 Comparison of regulatory submission processes with and without SCDM. A comparison of regulatory CMC submission assembly and dispatch is shown. Without SCDM, data is manually transcribed from the source into a technical report. The technical report is then used as a source document for a regulatory document, of which there are multiple regional variants created manually. Compilations of documents are then sent individually to health authorities for review, requiring the company to maintain multiple regional dossier variants. With SCDM, manual authoring steps can be reduced or eliminated as content and data can be taken directly from the source system, processed and semantically mapped via an enterprise data lake, and made available for incorporation in a regulatory filing via the structured content and data library, which is made up of content blocks. The content blocks can be reorganized, updated, and customized according to regulatory objectives and regional filing needs. The structured content and data library can achieve flexible output options, including electronic data submission, cloud-based information transfer, and printable paper-based filings some have the appropriate IT infrastructure to accept changes to include in the MAs or in post-approval fil - data in FHIR exchange format. SCDM tools enable the ings. The team files its MA first in one jurisdiction; At same datasets to be reused across a variety of outputs this time, two manufacturing sites A and B are included and file types, including paper, PDF, and FHIR-based but plans for a third site C are underway to meet pro- data submissions. SCDM ultimately provides a hierarchy jected demand. By the time the team files the MA in of inherent structure defined by semantic relationships additional jurisdictions, the final wave 1 countries, all between pieces of data which can be represented across sites are operational and thus included in the MA. The file formats and presentations. This flexibility is a key team can leverage SCDM to update the regional MAs aspect of SCDM’s utilization as it can accommodate var- in real-time based on manufacturing site readiness and ying levels of technological maturity across global regu- data availability. lators to simultaneously produce traditional (paper, PDF) After the wave 1 MA submissions, several hundred and data-driven submissions. SCDM would additionally information requests (IRs) are received from multi- streamline the MA process by ensuring that country-spe- ple agencies. It is advantageous for the sponsor to have cific summaries required by regulators can be completed traceable country-specific data to quickly and accurately accurately and expeditiously. provide a response to the agency requests given the time As the team is preparing the initial MAs for submis- constraints for IRs imposed by the various agency regu- sion, advancements in process development and manu- latory frameworks. With SCDM, all this information facturing are occurring simultaneously. As mentioned is readily available, as data on stability, comparability, earlier, scale-ups and site transfers may be needed to and number of lots manufactured is mapped to specific meet commercial and clinical supply chain require- applications and regions for which they were included. ments, resulting in complex tracking of these changes Without SCDM, it would be difficult to track what infor - across MAs and CTAs. The team must decide which mation was included for which country. B eierle et al. AAPS Open (2023) 9:11 Page 13 of 19 The use of prior knowledge and SCDM can provide SCDM helps the team to manage which submissions are structured content blocks to leverage related stability required for specific countries and updates the informa - data from similar products for justification in rapid deci - tion needed. This results in a more seamless rollout of the sion making. Since the timeline is accelerated, limited new presentation in pre-filled syringes which improves stability data are available from lots that can be justi- patient adherence and outcome. fied as primary stability lots per ICH definitions [87]. Ultimately, throughout the MA filing process, author - The team leverages prior knowledge from representative ing and submission timelines could be reduced by as products to refine the shelf-life analysis and model the much as 50% using SCDM in comparison to the tradi- stability profile for the candidate product. Additionally, tional process. Additional savings can be realized by ena- the use of SCDM enables updates to stability data simul- bling  faster filings in subsequent markets, thus reducing taneously in different submissions as they become avail - initial MA approval times in wave 2 regions to 4-5 years able. At the time of the initial MA filing, the team has as compared to a current average of 7-10 years. 12 months of stability data for two lots and 9 months for the third lot. A shelf-life at approval of at least 18 months The evolution of CMC submissions is proposed, and this generally requires real time data Until the creation of the ICH CTD, physical copies of from at least 3 representative lots to be provided dur- regulatory applications with unharmonized format- ing review. The filing team queries through the product- ting were shipped on pallets to major market agencies specific records and identifies two commercial products as illustrated schematically in Fig.  6. The physical logis - with similar manufacturing processes, formulations, tics and paper reviews in preparations for shipping the and structural characteristics, but with slightly different application pallets were a massive hurdle for companies SKUs and packaging configurations. One of the commer - in an increasingly globalized marketplace. The CTD as a cial products has 18 months of stability data while the harmonized work product was a valuable advancement other has 36 months. The team provides these stability that created a structure for regulatory submissions that data to supplement and model the predicted expiry sup- would be recognized by ICH member jurisdictions [88]. porting justification for a reasonable shelf-life at original However, the medium by which information was shared approval. With the use of SCDM, the product team can continued to be a physical paper copy. As technology supply these data to aid the approval process and are later evolved, the eCTD emerged moving a physical paper able to update filings in real-time once product-specific copy into an electronic structure and format. The ICH testing is completed.  eCTD was first adopted in 2003 by the EMA [89]. This After the product is approved, it becomes necessary transition from physical to electronic paper has made it to carefully manage the post-approval changes in each easier for regulatory agencies to review the submissions country such as the addition of a new manufacturing site. by providing the ability to hyperlink to different locations As shown in Fig.  4, the team is preparing wave 2 MAs within the structure of the eCTD. Sponsors benefited while also submitting manufacturing site C informa- from reduced allocation of resources to the preparation, tion to many of the wave 1 countries as a post-approval storage, and shipping of physical documents. The process change. SCDM can help by centrally storing all the site- was a favorable and noteworthy transition as the industry specific information through data elements that can then entered the twenty-first century, providing value to spon - be picked up and utilized for any one of the submissions. sors and health authorities by harmonizing the global Lastly, by using SCDM, the product team more effec - regulatory submission process. The industry and health tively manages a post-approval change to the product authorities can provide significant benefit to patients by presentation in all countries. The product is initially accelerating the logistics of regulatory submissions and approved as a once-weekly subcutaneous injection that the review processes through the use of digital technolo- is transported in vials and administered for 6 months. gies and adoption of an easily searchable and verifiable The once-weekly course of administration is burden - data-centric approach that would be superior to the doc- some for patients who must arrange transportation to ument-based eCTD. their healthcare provider’s office. This burden negatively The next milestone will be a move to cloud-based impacts adherence to the dosing regimen. After wave 1 submission systems with the use of targeted SCDM MA approvals, the sponsor optimizes the delivery with a components. Directing structured, verified source data new administration regimen which requires one injection components into regulatory submissions will enable tran- every month and is shipped as a pre-filled syringe. To this scendence beyond the eCTD. The cloud-based structure end, MAs for wave 2 countries will contain this presen- will contain “open” shared and “closed” restricted areas tation mode but wave 1 MAs will need to be updated with portals to control access within and between these according to each country’s reporting requirements. areas. This will promote concurrent and collaborative Beierle et al. AAPS Open (2023) 9:11 Page 14 of 19 Fig. 6 Summary of past, present, and future regulatory filing processes. While physical, paper-based submissions were the standard operating model in the past, the current regulatory framework in many major markets supports electronic submission of regulatory information in eCTD format. The conversion to an electronic system has ushered in multiple benefits, but there are ways to improve. In the future, electronic filings can achieve standardization and interoperability across data systems via HL7 FHIR, which is adapted for a real-time, cloud-based exchange ecosystem regulatory submissions and reviews between the spon- biopharmaceutical industry is struggling to determine sor, agencies, and third-party collaborators, with a focus how best to use current technologies in a highly regu- on reporting of data as opposed to document creation. lated environment [12]. Today, regulatory success for the This future state requires sponsor and regulatory agency biopharmaceutical sector remains solely dependent on endorsed collaborative efforts equivalent to the global the exchange of electronic or physical documents, limit- developments of the CTD and eCTD. Data-centered ing communication with health authorities to “in series” submissions can potentially advance inter-agency prod- transactions as illustrated in Fig. 1. uct discussions and provide CMC improved surveillance Health authority initiatives like KASA, PQ/CMC, ISO/ methods by accessing Module 3 data on demand for IDMP (SPOR), and ICH M4Q(R2) have the opportunity agency-related questions and thus drive more efficient to lead the way toward digitalization and globally aligned regulatory oversight. structured regulatory filings [77, 90–92]. Although these As the biopharmaceutical industry gravitates towards initiatives are in their early stages, they are providing the patient centricity, both sponsors and regulators must vital foundation for a modernized regulatory filing sys - continue to work not only to protect the safety of the tem. Both PQ/CMC and ISO/IDMP (SPOR) initiatives patient population but must also focus on deliver- are FHIR-based and provide a common global language ing and maintaining supply of therapies to patients in a for sponsors and health authorities to leverage for the more timely and efficient manner. Numerous industries secure exchange of electronic information. The align - have already leveraged twenty-first century technologies ment of the described health authority initiatives with to enhance speed and productivity [12]. However, the FHIR data exchange and a cloud-based ecosystem would B eierle et al. AAPS Open (2023) 9:11 Page 15 of 19 revolutionize regulatory filings, transcend the current aiding in supporting efficient data collection and there - capabilities of the ICH eCTD, and move the biopharma- fore improving regulatory discussion and collaboration ceutical industry into a modern application architecture. through natural language processing and vision applied Despite its many demonstrated advantages, there are to regulatory intelligence. As an example, AI could be some challenges related to SCDM implementation and harnessed to address responses to agency questions by use of cloud-based platforms that revolve around data drafting a response from content within the data lake localization, management, access, privacy, and legality and based on previous responses. At the post-approval [93]. Regulatory agencies want to preserve their auton- stage, AI implementation can be used in the industry to omy and companies need to ensure their intellectual learn continuously about each product change and more property (IP) is safeguarded. Decisions as to whether accurately identify higher and lower change-associated data will be centralized and managed by a third party, risks to better match regulatory reporting requirements or a hybrid method will need to be made. Standards including documentation. AI could learn from simi- will need to be put in place regarding system interoper- lar agency requests or questions made previously for ability and cybersecurity to protect patient and IP data other products, evaluate similarity between those prod- from breaches. Application programming interface (API) ucts, and use those prior knowledge data to assess the specifications will need to be structured such that each risk presented by a given change. Understanding of risk player in the regulatory ecosystem is only sharing what could potentially lower the reporting category for that is necessary and internal information is secure and pro- change. AI can be used together with other tools to pro- tected. Moreover, the systems will need to be built with vide essential information to a health authority including global compatibility in consideration. Region-specific data and modeling to support the risk assessment and legal hurdles will also need to be identified before imple - to mitigate existing risks. From a regulator’s perspec- mentation. Legal considerations regarding dataset server tive, AI can enable iterative learning about a particular localization, submission archival, and electronic verifica - change relative to other changes related to a product or tions will need to be addressed. different products or across sponsors. Health authorities Another challenge that hinders SCDM implementa- would also be able to take each sponsor’s distinct quality tion is that the current system requires further standardi- systems into account. SCDM would then be able to facili- zation and structuring. At present, long, unstructured tate the gathering of all available knowledge to assess the narratives are commonly included in the CMC sections risk of a particular change more appropriately in a sys- of the eCTD. Although these are intended to be data- tematic manner and thus evaluate the critical aspects of driven sections, companies may share more informa- its impact. tion and supplementary analysis than is necessary, often motivated by a desire to avoid future inquiries. Discus- Conclusion sions will need to be had to provide clear standardized Adoption and utilization of expedited regulatory review guidelines on what is and is not essential in the regula- pathways are increasing on a global scale. While this sup- tory decision-making process. Such conversations can be ports the acceleration of product availability for patients supported by regulators’ interest in developing risk-based with unmet medical needs, there are many efficiency and review algorithms, such as KASA [79]. Shorter, auto-gen- resource challenges that must be mitigated in acceler- erated summaries can be used to replace extensive narra- ated development environments. Navigating the myriad tives where applicable. This will allow for more effective regulatory requirements and timelines requires strategic resource allocation to the reviewing of essential data as coordination. opposed to reviewing extraneous text creating a more It is possible to accelerate drug development and efficient and nimble submission and review process. advance treatments to patients faster if product data, In the future, AI pattern recognition could be har- and data from applicable prior knowledge from other nessed for strategic planning as well as to track patient molecules, is managed more efficiently through a SCDM safety. AI-based technology is being adopted for phar- approach. The current system locks data for each prod - macovigilance to help with adverse event intake pro- uct into PDF documents which are manually generated, cessing and could potentially be used to assist with the verified, reviewed, published, and submitted. Health decision-making process for safety correlations [94, 95]. authorities must in turn manually retrieve submitted data Additionally, AI would be useful in searching through locked in PDF documents to be analyzed and compiled data to identify patterns in agency requests for further into their systems. This is a laborious, inefficient, and information, establish precedent in regulatory decision error-prone process. Sourcing prior knowledge data from making, and help seek consistency in agency reviews separate product dossiers is a particular challenge for a [96]. AI in regulatory may begin streamlining work by document-based system. Employing SCDM would mean Beierle et al. AAPS Open (2023) 9:11 Page 16 of 19 FIH First in human that structured data blocks can be deployed to relevant FDA Food and Drug Administration sections of the eCTD and could even be employed across FDASIA Food and Drug Administration Safety and Innovation Act different product eCTD sections. This process would HL7 Health Level 7 IDMP Identification of Medicinal Product ensure data integrity and traceability, making it more IR Information request amenable to the use of tools like modeling. A stepwise IT Information technology approach to implementing SCDM in regulatory submis- ICMRA International Coalition of Medicines Regulatory Authorities ICH International Council for Harmonization of Technical Require- sions can be envisioned. ments for Pharmaceuticals for Human Use Sponsors, regulators, and patients all share the same ISO International Organization for Standardization goal: faster access to safe and effective treatments. IND Investigational new drug KASA Knowledge-Aided Assessment and Structured Application Towards this common goal, sponsors, health authori- LIMS Laboratory Information Management Systems ties, and third-party organizations need to work together MAPP Manual of Policies and Procedures to develop the infrastructure and supportive regulatory MA Marketing application NDA New Drug Application policies needed to enable the utilization of information OCE Oncology Center of Excellence technology to accelerate the preparation, submission, and OMS Organisation Management Services review of regulatory filings. The vision for an efficient and PQ/CMC Pharmaceutical Quality/Chemistry, Manufacturing, and Controls PDUFA Prescription Drug User Fee Act expedited regulatory submissions process is the use of PRIME Priority Medicines SCDM in single-sourced filings and collaborative agency PLM Product Lifecycle Management reviews, with manual submission tasks replaced by auto- PMDA P harmaceuticals and Medical Devices Agency PMS Product Management Services populated filings, assisted by system interoperability and RTOR Real-time Oncology Review API integration in a cloud-based exchange platform. A RMAT Regenerative Medicine Advanced Therapy cloud-based submission system with SCDM integra- SaaS Software as a Service SOP Standard Operating Procedure tion which allows sponsors to reuse information with- SPOR Substance, Product, Organization and Referentials out the need to generate PDF documents will provide a TMAP Technology Modernization Action Plan more seamless submission and lifecycle management UK United Kingdom US United States process. Health authorities will be empowered to make better decisions, based on data that is more traceable, Authors’ contributions reliable, and transparent. CMC data is used, updated, and All authors have contributed equally on writing, editing, and reviewing the manuscript submitted. All author(s) read and approved the final manuscript. reused hundreds if not thousands of times throughout a product’s lifecycle. Improved management of these data Declarations and its usability can propel therapeutic innovation into the future. It is up to sponsors and regulators to work Availability of data and materials together and build this new infrastructure that enables Not applicable. acceleration by eliminating underlying inefficiencies. It is Competing interests imperative that patient treatment should not be delayed Jill Beierle, Marquerita Algorri, Marisol Cortés, Nina S. Cauchon, Andrew because of outdated regulatory document preparation Lennard, J. Paul Kirwan, Shirley Oghamian, and Michael J. Abernathy reports financial support which was provided by Amgen Inc. and submission systems. Funding This research did not receive any specific grant from funding agencies in the Abbreviations public, commercial, or not-for-profit sectors. API Application programming interface AI Artificial intelligence Acknowledgements ANDA Abbreviated New Drug Application The authors would like to thank Gerd Kleemann, Gino Grampp, Jason H. BTD Breakthrough therapy designation Binder, Pablo Rolandi, Eric Jordan, and Nitin Rathore for their helpful sugges- CBER Center for Biologics Evaluation and Research tions throughout development of this manuscript. CDER C enter for Drug Evaluation and Research CMC Chemistry, Manufacturing, and Controls CDRP Chemistry, Manufacturing, and Controls Development and Readi- Received: 1 February 2023 Accepted: 27 March 2023 ness Pilot CTA Clinical trial application CTD Common technical document CEA Conditional early approval CMA Conditional marketing authorization References DADI Digital Application Dataset Integration 1. Berdel WE (2021) Unintended regulatory caused early death-a difficult eAF Electronic application form endpoint in cancer patient care and treatment. Cancers (Basel) 13(6):1457 eCTD Elec tronic common technical document 2. Friedersdorf C (2021) The death toll of delay. The Atlantic. Available from: ELN Electronic Lab Notebooks https:// www. theat lantic. com/ ideas/ archi ve/ 2021/ 08/ fda- delays- carry- EMA European Medicines Agency death- toll/ 619871/ FHIR Fast Healthcare Interoperability Resources B eierle et al. AAPS Open (2023) 9:11 Page 17 of 19 3. Helwick C (2015) Delays in drug approval are deadly, highlighting the need eering/ janua ry- febru ary- 2022/ toward- single- global- contr ol- strat egy- for improved regulatory efficiency. The ASCO Post. Available from: https:// indus try ascop ost. com/ issues/ octob er- 25- 2015/ delays- in- drug- appro val- are- 18. FDA (1988) Available from: https:// archi ves. feder alreg ister. gov/ issue_ deadly- highl ighti ng- the- need- for- impro ved- regul atory- effic iency/slice/ 1988/ 10/ 21/ 41492- 41527. pdf# page= 25. Accessed 13 Jan 2023 4. Potter CJ, Yuan H, Cauchon NS, Chang LL, Blaettler D, Kin DW, Millili PG, 19. FDA. Guidance for Industry Expedited Programs for Serious Conditions - Mazzola G, Ocheltree T, Tyler SM, Taber G, Watson TJ (2019) Accelerated Drugs and Biologics (2014) Available from: https:// www. fda. gov/ media/ Pharmaceutical product development, registration, commercialization, 86377/ downl oad. Accessed 22 Aug 2022 and life cycle CMC lessons, Part 1. Pharmaceutical Engineering. Available 20. FDA. Advancing Health Through Innovation: New Drug Therapy Approvals from: https:// ispe. org/ pharm aceut ical- engin eering/ ispeak/ accel erated- CDER 2021 Available from: https:// www. fda. gov/ media/ 155227/ downl pharma- produ ct- devel opment- regis trati on oad. Accessed 20 Aug 2022 5. Potter CJ, Yuan H, Cauchon NS, Chang LL, Blaettler D, Kin DW, Millili PG, 21. FDA. CBER Regenerative Medicine Advanced Therapy (RMAT ) Approvals Mazzola G, Ocheltree T, Tyler SM, Taber G, Watson TJN (2019) Accelerated (2022) Available from: https:// www. fda. gov/ vacci nes- blood- biolo gics/ pharmaceutical: product development, registration, commercialization & cellu lar- gene- thera py- produ cts/ cber- regen erati ve- medic ine- advan ced- life cycle CMC lessons, Part 2. Pharmaceutical Engineering. Available from: thera py- rmat- appro vals. Accessed 25 Aug 2022 https:// ispe. org/ pharm aceut ical- engin eering/ accel erated- pharm aceut 22. Algorri M, Acharya A, Bernstein J, Cauchon NS, Chen XH, Huynh-Ba K, ical- produ ct- devel opment- regis trati on Krantz C, Tao Li YL 6, McLamore S, Roberts SW, Schwinke D, Shah R, 6. Dye III, Groskoph ESJG, Kelley B, Millili GP, Nasr MM, Potter CJ, Thostesen Schirmer A, Strickland H, Tang K, Watson T (2022) 19 Meeting Report: ES, Vermeersch H (2015) CMC Considerations when a Drug Development Advancing Accelerated Regulatory Review with Real-Time-Oncology Review Project is Assigned Breakthrough Therapy Status Pharmaceutical Engineer- (RTOR), Project Orbis, and the Product Quality Assessment Aid AAPS Open 8 ing. Available from: https:// ispe. org/ pharm aceut ical- engin eering/ janua Available from: https:// aapso pen. sprin gerop en. com/ artic les/https:// doi. ry- febru ary- 2015/ cmc- consi derat ions- when- drug- devel opment- proje ct#: org/ 10. 1186/ s41120- 022- 00066-1 ~: text= CMC% 20Con sider ations% 20when% 20a% 20Drug% 20Dev elopm 23. FDA. Real-time review of drug applications is now a reality (2018) 18 Sept. ent% 20Pro ject% 20is% 20Ass igned% 20Bre akthr ough% 20The rapy% 20Sta Available from: https:// www. fda. gov/ drugs/ real- time- review- drug- appli tus,- Earl% 20S. & text= Assig nment% 20of% 20Bre akthr ough% 20The rapy% catio ns- now- reali ty- septe mber- 20- 2018- issue. Accessed 22 Aug 2022 20(BT,a% 20% E2% 80% 9Ccon venti onal% E2% 80% 9D% 20dev elopm ent% 24. Feng C, Virparia R, Mui ET (2021) Analysis of the real-time oncology 20pro gram review (RTOR) pilot program for approvals of new molecular entities. Ther 7. Algorri M, Cauchon NS, Abernathy MJ (2020) Transitioning chemistry, Innov Regul Sci 55(4):881–888 manufacturing, and controls content with a structured data man- 25. EMA. Conditional marketing authorization. Available from: https:// www. agement solution: streamlining regulatory submissions. J Pharm Sci ema. europa. eu/ en/ human- regul atory/ marke ting- autho risat ion/ condi 109(4):1427–1438tional- marke ting- autho risat ion. Accessed 29 Aug 2022 8. Gardner N (2021) Data integrity and pharma 4.0. Available from: https:// 26. EMA. Orphan designation: marketing authorization. Available from: https:// www.thermofisher.com/blog/connectedlab/data-integrity-and-pharma-www. ema. europa. eu/ en/ human- regul atory/ marke ting- autho risat ion/ 4-0/?ce=E.22CMD.DS109 .06571.01&cid=E.22CMD.DS109.06571.01&iq=orphan- desig nation- marke ting- autho risat ion. Accessed 29 Aug 2022 IQLAAKGACZFALKMAXR&ef_id=CjwKCAjw1ICZBhAzEiwAFfvFhHai57BU 27. EMA. Accelerated assessment. Available from: https:// www. ema. europa. eu/ POSeo3z7VRyDsgbU6Pdbm7yrVFn_C2Csbn86fzPaCwhjARoCUvsQAvD_en/ human- regul atory/ marke ting- autho risat ion/ accel erated- asses sment. BwE:G:s&s_kwcid=AL!3652!3!563674789876!p!!g!!pharma%204.0&gclid Accessed 29 Aug 2022 =CjwKCAjw1ICZBhAzEiwAFfvFhHai57BUPOSeo3z7VRyDsgbU6Pdbm7yr 28. EMA. PRIME: priority medicines. Available from: https:// www. ema. europa. VFn_C2Csbn86fzPaCwhjARoCUvsQAvD_BwE. Accessed 10 Jan 2023eu/ en/ human- regul atory/ resea rch- devel opment/ prime- prior ity- medic 9. Reinhardt IC, Oliveira J, Ring D (2023) Industry 4.0 & the future of the phar- ines. Accessed 29 Aug 2022 maceutical industry. Pharmaceutical Engineering. Available from: https:// 29. EMA. Compassionate use. Available from: https:// www. ema. europa. eu/ en/ ispe. org/ pharm aceut ical- engin eering/ march- april- 2021/ indus try- 40- human- regul atory/ resea rch- devel opment/ compa ssion ate- use. Accessed future- pharm aceut ical- indus try. Accessed 10 29 Aug 2022 10. International Society of Pharmaceutial Engineering (ISPE). Pharma 4.0 30. Vreman RA, Heikkinen I, Schuurman A, Sapede C, Garcia JL, Hedberg N, Available from: https:// ispe. org/ initi atives/ pharma- 4.0. Accessed 13 Sept Athanasiou D, Grueger J, Leufkens HGM, Goettsch WG (2019) Unmet 2022 Medical need: an introduction to definitions and stakeholder percep - 11. QbDVision. (2020) ICH, QbD, Pharma 4.0: One and the Same. Available from: tions. Value in Health 22(11):1275–1282 https:// www. qbdvi sion. com/ ich- qbd- pharma/. Accessed 22 Aug 2022 31. EMA. Annual Report (2021) Available from: https:// www. ema. europa. eu/ 12. Ahluwalia K, Abernathy MJ, Beierle J, Cauchon NS, Cronin D, Gaiki S, Len-en/ docum ents/ annual- report/ 2021- annual- report- europ ean- medic ines- nard A, Mady P, McGorry M, Sugrue-Richards K, Xue G (2021) The future agency_ en. pdf. Accessed 13 Jan 2022 of CMC regulatory submissions: streamlining activities using structured 32. EMA (2022) EMA initiatives for acceleration of development support and content and data management. J Pharm Sci 111(5):1232–1244 evaluation procedures for COVID-19 treatments and vaccines. Available 13. Helfand C (2019) If pharma looks slow to adopt AI, it’s got good reason, from: https:// www. ema. europa. eu/ en/ docum ents/ other/ ema- initi atives- expert says. FIERCE Pharma. Available from: https:// www. fierc ephar ma. accel erati on- devel opment- suppo rt- evalu ation- proce dures- covid- 19- com/ marke ting/ if- pharma- looks- slow- to- adopt- ai- there-s- good- reason- treat ments- vacci nes_ en. pdf. Accessed 13 Jan 2023 expert. Accessed 12 Jan 2023 33. Marinus R, Mofid S, Mpandzou M, Kühler TC (2022) Rolling reviews during 14. Manzano T, Canals A (2022) Measuring Pharma’s Adoption of Industry 4.0. COVID-19: the European Union experience in a global context. Clin Ther Pharmaceutical Engineering. Available from: https:// ispe. org/ pharm aceut 44(3):352–363 ical- engin eering/ janua ry- febru ary- 2022/ measu ring- pharm as- adopt ion- 34. PMDA (2021) Expedited regulatory pathways in Japan. Available from: indus try- 40https:// www. youtu be. com/ watch?v= P6z3M GDhYh4. Accessed 13 Jan 15. Hwang TJ, Darrow JJ, Kesselheim AS (2017) The FDA’s expedited pro- 2023 grams and clinical development times for novel therapeutics, 2012–2016. 35. Tanaka M, Idei M, Sakaguchi H, Kato R, Sato D, Sawanobori K, Kawarasaki JAMA 318(21):2137–2138 S, Hata T, Yoshizaki A, Nakamura M, Ikuma M (2021) Achievements and 16. Friends of Cancer Research (2023) Modernizing expedited development challenges of the Sakigake designation system in Japan. Br J Clin Pharma- programs. Friends of Cancer Research Annual Meeting 2020. Available col 87(10):4027–4035 from: https:// frien dsofc ancer resea rch. org/ wp- conte nt/ uploa ds/ Moder 36. MHLW (2020) Notification: PSEHB/PED No. 0831/6: handling of designa- nizing_ Exped ited_ Devel opment_ Progr ams- 2020_0. pdf. Accessed 12 tion of pioneer drugs 17. Beierle J, Cauchon NS, Graul TW, Hedberg Y, Holm MB, Lepore JV, 37. De Claro RA, Spillman D, Hotaki LT, Shum M, Mouawad LS, Santos GML, MacKenzie R, Mistry K, Qian X, Robinson K, Rullo G, Tang KT, Watson T Robinson K, Hunt M, Healy C, Chan A, Looi YH, Rodrigues C, Rohr UP, (2022) Toward a single global control strategy: industry study Pharmaceu- Walther C, Pazdur R (2020) Project Orbis: Global Collaborative Review tical Engineering. Available from: https:// ispe. org/ pharm aceut ical- engin Program Clin Cancer Res 26(24):6412–6416 Beierle et al. AAPS Open (2023) 9:11 Page 18 of 19 38. FDA. Project Orbis (2022) Available from: https:// www. fda. gov/ about- fda/ 55. IBM. What is a data fabric? Available from: https:// www. ibm. com/ topics/ oncol ogy- center- excel lence/ proje ct- orbis. Accessed 29 Aug 2022data- fabric. Accessed 14 Sept 2022 39. ICMRA. Pharmaceutical quality - regulatory collaboration pilots: call for 56. ArborSys. Structured content management solutions. Available from: http:// industry applications Available from: https:// icmra. info/ drupal/ strat egici www. arbor sys. com/ struc tured- conte nt- manag ement- solut ions. html. nitat ives/ pqkms/ pq_ pilots_ call_ for_ indus try_ appli catio ns. Accessed 29 Accessed 30 Aug 2022 Aug 2022 57. DitaExchange. Structured content management for financial services. Avail- 40. ICMRA (2022) A regulatory pharmaceutical quality knowledge manage- able from: https:// ditae xchan ge. com/ finan cial- servi ces/. Accessed 30 ment system (PQ KMS) to enhance the availability of quality medi- Aug 2022 cines. Available from: https:// www. icmra. info/ drupal/ strat egici nitat ives/ 58. ESKO. Customer case studies. Available from: https:// www. esko. com/ en/ pqkms/ joint_ refle ction_ paper . Accessed 16 Sept 2022brands/ case- studi es. Accessed 30 Aug 2022 41. ICMRA. International Coalition of Medicines Regulatory Authorities (2022) 59. OpenText . Read customer success stories. Available from: https:// www. Available from: https:// icmra. info/ drupal/ en. Accessed 29 Aug 2022opent ext. com/ custo mers. Accessed 30 Aug 2022 42. ICMRA. ICMRA-industry virtual workshop report on enabling manufactur- 60. Richardson M (2022) Data management matters. Aerospace Manufactur- ing capacity in the COVID-19 pandemic (2021) Available from: https:// ing 2020 23 November 2020. Available from: https:// www. aero- mag. www. icmra. info/ drupal/ sites/ defau lt/ files/ 2021- 10/ covid- 19_ manuf actur com/ data- manag ement- matte rs/. Accessed 30 ing_ capac ity_ ws_ report. pdf. Accessed 10 Jan 2023 61. Studer S Component content management use cases. Zia Consulting 2020 43. An Industry proposal: recommendations to support the rapid increase of 22 Apr 2020. Available from: https:// www. ziaco nsult ing. com/ compo manufacturing capacity for the production of COVID-19 therapeutics and nent- conte nt- manag ement/ use- cases/. Accessed 14 Aug 2022 vaccines. ICMRA workshop on enabling manufacturing capacity in the 62. Cognition (2022) Why pharmaceutical companies look to lighthouse to gen- COVID-19 pandemic 2021 28 June Available from: https:// www. ifpma. erate electronic reports for CMC-related submissions Available from: https:// org/ wp- conte nt/ uploa ds/ 2021/ 07/ Indus try_ Propo sal_ Mfg_ Capac ity_ fs. hubsp otuse rcont ent00. net/ hubfs/ 250507/ Why% 20Pha rmace utical% COVID- 19- v18Fe b2021_ revJu ne2021. pdf. Accessed 2220Com panies% 20Look% 20to% 20Lig hthou se% 20to% 20Gen erate% 20Ele 44. EMA. Welcome to IRIS. Available from: https:// iris. ema. europa. eu/. ctron ic% 20Rep orts% 20for% 20CMC- relat ed% 20Sub missi ons_ Drug% 20Sta Accessed 02 Sept 2022bility_ Cogni tion% 20Cor porat ion_ Janua ry% 202022. pdf. Accessed 14 July 45. Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, Bi Y, Liu J, 2022 Rahman A, Wearne E, Ojofeitimi I, Hotaki LT, Spillman D, Pazdur R, Beaver 63. Docuvera Efficiently create and update CMC documentation throughout JA, Singh H (2022) FDA approval summary: sotorasib for KRAS G12C- the entire pharmaceutical manufacturing process. Available from: https:// mutated metastatic NSCLC. Clin Cancer Res 28(8):1482–1486docuv era. com/ chemi cal- manuf actur ing- and- contr ols/. Accessed 30 Aug 46. Popkin ME, Goese M, Wilkinson D, Finnie S, Flanagan T, Campa C, Clinch A, 2022 2022 Teasdale A, Lennard A, Cook G, Mohan G, Osborne MD (2022) Chemistry 64. QbDVision. Discover all your knowledge can do Available from: https:// manufacturing and controls development, industry reflections on manu-www. qbdvi sion. com/ struc tured- platf orm/ facture and supply of pandemic therapies and vaccines. AAPS J. 24(6):101 65. Veeva IDMP Readiness Center. Available from: https:// www. veeva. com/ 47. EMA. Toolbox guidance on scientific elements and regulatory tools to produ cts/ vault- platf orm/ vault- rim- idmp- resou rce- hub/ support quality packages for PRIME and certain marketing authorisation 66. Lorenz Product information and lifecycle management with LORENZ applications targeting an unmet medical need (2022) Available from: drugTrack. Available from: https:// www. lorenz. cc/ Solut ions/ idmp/ https:// www. ema. europa. eu/ en/ docum ents/ scien tific- guide line/ toolb 67. GitHub IDG (2022) Automate your workflow from idea to production. Avail- ox- guida nce- scien tific- eleme nts- regul atory- tools- suppo rt- quali ty- data- able from: https:// github. com/ featu res/ issues. Accessed November 29 packa ges- prime- certa in_ en. pdf 2022 48. FDA. PDUFA reauthorization performance goals and procedures fiscal 68. Tranchard S (2017) Revised IDMP standards to improve description of year 2023 through 2027 (2022) Available from: https:// www. fda. gov/ medicinal products worldwide. ISO. Available from: https:// www. iso. org/ media/ 151712/ downl oad. Accessed 10 Aug 2022news/ ref22 34. html 49. Food and Drug Administration Federal Register. Quality Management 69. EMA. Substance, product, organisation and referential (SPOR) master data. Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Available from: https:// www. ema. europa. eu/ en/ human- regul atory/ resea Product Manufacturers; Program Announcement (2020) Available from: rch- devel opment/ data- medic ines- iso- idmp- stand ards/ subst ance- produ https:// www. feder alreg ister. gov/ docum ents/ 2020/ 10/ 16/ 2020- 22976/ ct- organ isati on- refer ential- spor- master- data quali ty- manag ement- matur ity- for- finis hed- dosage- forms- pilot- progr am- 70. Miglierini G (2022) The transition towards EMA’s new Digital Appliation for- domes tic- drug- produ ct. Accessed 10 Dec 2022 Dataset Integration (DADI) user interface. EIPG. Available from: https:// eipg. 50. FDA. Manual of Policies and Procedures MAPP 5015.13 “Quality assess-eu/ the- trans ition- towar ds- ema- new- digit al- appli cation- datas et- integ ment for products in expedited programs” (2022) Available from: https:// ration- dadi/ www. fda. gov/ media/ 162786/ downl oad. Accessed 9 Jan 2023 71. Brennan Z (2017) FDA looks to standardize PQ/CMC data and terminolo- 51. EMA. Meeting Report: Joint BWP/QWP workshop with stakeholders in gies. Regulatory Focus. Available from: https:// www. raps. org/ regul atory- relation to prior knowledge and its use in regulatory applications (2018) focus% E2% 84% A2/ news- artic les/ 2017/7/ fda- looks- to- stand ardize- pq- Available from: https:// www. ema. europa. eu/ en/ docum ents/ report/ meeti cmc- data- and- termi nolog ies ng- report- joint- biolo gics- worki ng- party/ quali ty- worki ng- party- works 72. FDA (2022) Draft pharmaceutical quality/chemistry manufacturing and hop- stake holde rs- relat ion- prior- knowl edge- its- use- regul atory- appli catio controls (PQ/CMC) data exchange. Available from: https:// www. fda. gov/ ns_ en. pdfmedia/ 157085/ downl oad. Accessed 16 52. EMA. Toolbox guidance on scientific elements and regulatory tools to 73. FDA (2022) Draft pharmaceutical quality chemistry manufacturing and support quality data packages for PRIME and certain marketing authori- controls (PQCMC) data exchange. SUPPORTING & RELATED MATE- sation applications targeting an unmet medical need (2022) 22 April RIAL. Available from: https:// www. regul ations. gov/ docum ent/ FDA- 2022- 2022. Available from: https:// www. ema. europa. eu/ en/ docum ents/ scien N- 0297- 0002. Accessed 17 Sept 2022 tific- guide line/ toolb ox- guida nce- scien tific- eleme nts- regul atory- tools- 74. HL7 (2022) Introducing HL7 FHIR. Available from: https:// hl7. org/ FHIR/ suppo rt- quali ty- data- packa ges- prime- certa in_ en. pdfsumma ry. html. Accessed 30 Aug 2022 53. EMA. Meeting Report: Workshop with stakeholders on support to quality 75. HL7 (2022) Code systems. Available from: https:// hl7. org/ FHIR/ termi nolog development in early access approaches (i.e. PRIME, Breakthrough Thera-ies- syste ms. html. Accessed 30 pies) (2018) Available from: https:// www. ema. europa. eu/ en/ docum ents/ 76. Eglovitch JS (2021) FDA taking incremental approach to launching KASA report/ report- works hop- stake holde rs- suppo rt- quali ty- devel opment- reviews. Regulatory Focus. Available from: https:// www. raps. org/ news- early- access- appro aches- ie- prime_ en. pdfand- artic les/ news- artic les/ 2021/ 11/ fda- taking- incre mental- appro ach- to- 54. Macdonald JC, Isom DC, Evans DD, Page KJ (2021) Digital innovation in launc hing- kasa medicinal product regulatory submission, review, and approvals to create 77. IPQ. FDA’s KASA and related PQ/CMC initiatives on improving CMC data a dynamic regulatory ecosystem-are we ready for a revolution? Front structuring and sharing will help support ICH M4Q revision. 2022 17 Feb Med (Lausanne) 8:660808 2022. Available from: https:// ipq. org/ fdas- kasa- and- relat ed- pq- cmc- initi B eierle et al. AAPS Open (2023) 9:11 Page 19 of 19 atives- on- impro ving- cmc- data- struc turing- and- shari ng- will- help- suppo Publisher’s Note rt- ich- m4q- revis ion/ Springer Nature remains neutral with regard to jurisdictional claims in pub- 78. Kozlowski S, FDA/PQRI Conference on Advancing Product Quality 2021 lished maps and institutional affiliations. Knowledge-Aided and Structured Application (KASA) and Pharmaceutical Quality/CMC (PQ/CMC) Update:KASA for Biologics. 5th. Available from: https:// pqri. org/ wp- conte nt/ uploa ds/ 2021/ 12/3- PQRI- KASA- for- Biolo gics_ 12-3- 21_ SKozl owski- FINAL- v1. pdf 79. Roelofs B What’s in a KASA? Knowledge-aided assessment and structured application (KASA) for biological products. Well Characterized Biotechnol- ogy Products WCBP 2022. Available from: https:// www. casss. org/ docs/ defau lt- source/ wcbp/ 2022- wcbp- speak er- prese ntati ons/ speak er- prese ntati ons- roelo fs- brian- cder- fda- 2022. pdf? sfvrsn= bdc8a 079_8 80. HLA FHIR. Data exchange industry – pharmaceutical quality (dx-PQ) (2020) Available from: https:// build. fhir. org/ ig/ HL7/ uv- dx- pq/ backg round. html 81. Tarius (2017) SAC Tracker Pharmaceutical Science and Clinical Pharmacol- ogy Advisory Committee. Available from: http:// www. sac- track er. com/ pscp- 20180 920- ba 82. Yu LX, Raw A, Wu L, Capacci-Daniel C, Zhang Y, Rosencrance S (2019) FDA’s new pharmaceutical quality initiative: knowledge-aided assess- ment & structured applications. Int J Pharmaceutics: X 1:100010 83. FDA. Modernization in Action 2022 (2022) Available from: https:// www. fda. gov/ files/ about% 20fda/ publi shed/ Moder nizat ion_ in_ Action_ 2022. pdf 84. EMA. European Medicines Agency Cloud Strategy (2022) Available from: https:// www. ema. europa. eu/ en/ docum ents/ other/ europ ean- medic ines- agency- cloud- strat egy- accel erati ng- innov ation- digit alisa tion- better- public- anima l_. pdf 85. EMA. Q&As on IRIS registration, login and RPI requests. Available from: https:// iris. ema. europa. eu/ forums/ whats- new/ b9e93 2c2- 3ad7- ea11- bf21- 0003 ff5fd6 3e. Accessed 02 Sept 2022 86. Nogueira F (2022) Welcome to Accumulus Synergy. Available from: https:// www. accum ulus. org/. Accessed 9 87. ICH. ICH Topic Q 1 A (R2) stability testing of new drug substances and products (2003) Available from: https:// www. ema. europa. eu/ en/ docum ents/ scien tific- guide line/ ich-q- 1- r2- stabi lity- testi ng- new- drug- subst ances- produ cts- step-5_ en. pdf 88. ICH (2022) History. Available from: https:// www. ich. org/ page/ histo ry. Accessed 17 89. Mezher M (2016) Going digital: EMA to ditch paper, require electronic application forms RAPS February 26, 2015. Available from: https:// www. raps. org/ regul atory- focus% E2% 84% A2/ news- artic les/ 2015/2/ going- digit al- ema- to- ditch- paper ,- requi re- elect ronic- appli cation- forms 90. EMA. Introduction to ISO identification of medicinal products, SPOR programme (2016) EMA/732656/2015. Available from: https:// www. ema. europa. eu/ en/ docum ents/ other/ intro ducti on- iso- ident ifica tion- medic inal- produ cts- spor- progr amme_ en. pdf. Accessed 17 Jan. 2023 91. FDA. Pharmaceutical quality/chemistry, manufacturing & controls (PQ/CMC). Available from: https:// www. fda. gov/ indus try/ fda- data- stand ards- advis ory- board/ pharm aceut ical- quali tyche mistry- manuf actur ing- contr ols- pqcmc. Accessed 3 Aug 2022 92. ICH. M4Q(R2) Common technical document on quality guideline (2021) Available from: https:// datab ase. ich. org/ sites/ defau lt/ files/ ICH_ M4Q- R2_ Conce ptPap er_ Endor sed_ 2021_ 1115. pdf 93. Robertson AS, Malone H, Bisordi F, Fitton H, Garner C, Holdsworth S, Honig P, Hukkelhoven M, Kowalski R, Milligan S, O’Dowd L, Roberts K, Rohrer M, Stewart J, Taisey M, Thakkar R, Van Baelen K, Wegner M (2020) Cloud-based data systems in drug regulation: an industry perspective. Nat Rev Drug Discov 19(6):365–366 94. Murali K, Kaur S, Prakash A, Medhi B (2019) Artificial intelligence in phar - macovigilance: practical utility. Indian J Pharmacol 51(6):373–376 95. Pfizer (2022) AI in drug safety: building the elusive ‘Loch Ness Monster’ of reporting tools. Available from: https:// www. pfizer. com/ news/ artic les/ ai- drug- safety- build ing- elusi ve-% E2% 80% 98loch- ness- monst er% E2% 80% 99- repor ting- tools. Accessed 16 96. Regulatory Affairs Professionals Society. RF Quarterly, Artificial intelligence (2022) December Available from: https:// www. raps. org/ news- and- artic les/ news- artic les/ 2022/ 11/ rf- quart erly- decem ber- 2022- arti ficial- intel ligen ce. Accessed 14 Jan 2023 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AAPS Open Springer Journals

Structured content and data management—enhancing acceleration in drug development through efficiency in data exchange

Loading next page...
 
/lp/springer-journals/structured-content-and-data-management-enhancing-acceleration-in-drug-1ncOB86g7n

References (154)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2023
eISSN
2364-9534
DOI
10.1186/s41120-023-00077-6
Publisher site
See Article on Publisher Site

Abstract

Innovation in pharmaceutical therapeutics is critical for the treatment of serious diseases with unmet medical need. To accelerate the approval of these innovative treatments, regulatory agencies throughout the world are increasingly adopting the use of expedited pathways and collaborative regulatory reviews. These pathways are primarily driven by promising clinical results but become challenging for Chemistry, Manufacturing, and Controls (CMC) information in regulatory submissions. Condensed and shifting timelines present constraints that require new approaches to the management of regulatory filings. This article emphasizes technological advances that have the potential to tackle the underlying inefficiencies in the regulatory filing eco-system. Structured content and data management (SCDM) is highlighted as a foundation for technologies that can ease the burden on both sponsors and regulators by streamlining data usage in regulatory submissions. Re-mapping of information technology infrastructure will improve the usability of data by moving away from document-based fil- ings towards electronic data libraries. Although the inefficiencies of the current regulatory filing eco-system are more evident for products that are filed using expedited pathways, it is envisioned that the more widespread adoption of SCDM, across standard filing and review processes, will improve overall efficiency and speed in the compilation and review of regulatory submissions. Keywords Regulatory science, Standards, Structure, Stability, Automation, Acceleration pathway, Chemistry manufacturing and controls, Structured content data management, Cloud-based systems processes are necessary in order to ensure product safety, Introduction efficacy, and quality, the staggered and prolonged time - The pharmaceutical industry is complex and highly regu - lines required for global approvals contribute to delays in lated, since global health authorities and biopharmaceuti- patient access to lifesaving medicines [1–3]. To expedite cal companies are mutually responsible for ensuring that product availability for indications with unmet medical marketed pharmaceutical products are safe and effica - need or serious illness, accelerated regulatory approval cious. While thorough regulatory review and approval pathways have been established in several different regions. *Correspondence: While these expedited regulatory pathways can result Jill Beierle in accelerated filings and, in some instances, faster naclhoh@gmail.com Department of Global Regulatory Affairs and Strategy – CMC, Amgen review/approval timelines, they require significant Inc, CA 91320 Thousand Oaks, USA resources, coordination, and program management for Department of Physiology, Johns Hopkins University School both regulators and sponsors. The use of these path - of Medicine, Baltimore, MD 21205, USA ways is often based on promising results from clinical © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Beierle et al. AAPS Open (2023) 9:11 Page 2 of 19 development but poses significant challenges for Chem - This article intends to highlight how SCDM and asso - istry, Manufacturing, and Controls (CMC) development ciated technologies can work synergistically with fast- and data in regulatory submissions [4–6]. For many tracked products to help address the regulatory CMC regions, the current regulatory process requires that challenges inherent in an accelerated development envi- CMC data be supplied primarily in Module 3 of the com- ronment. A summary of expedited regulatory pathways mon technical document (CTD) or electronic (e)CTD, and collaborative review processes is provided with dis- which consists of an XML backbone structure that pri- cussion on their specific challenges. Information on key marily houses PDF documents containing data, descrip- advancements in technologies that are supportive of tions, reports, and relevant certifications. The process of SCDM in regulatory submissions is also summarized. A compiling and maintaining CMC information and data in hypothetical case study, representative of a fictional filing document format requires substantial manual input and scenario, is presented to demonstrate how SCDM could rework throughout a product’s lifecycle, which is particu- potentially be applied to meet the challenges associated larly problematic for products undergoing accelerated with expedited product filings at various stages in devel - development with multiple simultaneous submissions at opment. Lastly, the future outlook is discussed. varying stages of development. Enhancing data manage- ment efficiency for regulatory submissions can help alle - Expedited regulatory pathways improve patient viate delays and reduce data entry errors by streamlining access to new medicines repetitive authoring tasks, structuring information to The decision to pursue an expedited review pathway allow for automation, and enabling data-driven submis- with a particular health authority is typically associated sion assembly and review [7]. with success in early-stage clinical development trials Towards this goal, the last few decades have fostered and demands earlier regulatory agency engagement in significant technological advancements within the phar - the development program as well as alignment on CMC maceutical industry, such as the International Society of considerations and filing expectations [15, 16]. Notably, Pharmaceutical Engineering (ISPE) Pharma 4.0 which novel modalities or therapies will need added collabora- includes incorporation of technologies including cloud tive discussions across quality, clinical, and non-clinical computing, big data analytics, Internet of Things (IoT), disciplines within health agencies. A barrier to speedy and artificial intelligence (AI), while supporting regula - access to new medicines for patients globally is the lack tory best practices [8–10]. While Pharma 4.0 encom- of harmonization in regulatory requirements, including passes a transformative model of manufacturing enabled those that impact accelerated filing pathways. Achieving by modern technology which complements Quality by an expedited approval designation in one country does Design (QbD) principles [11], in general, the pharma- not guarantee that it will be granted elsewhere [17]. A ceutical industry has been slow to adopt the necessary summary of accelerated review pathways in several major technological advancements in information systems that markets is presented below. enable modernization of information exchange and data The need to accelerate the availability of new therapeu - management. Structured content and data management tics was enacted in the United States (US) in 1988 by the (SCDM), which allows information to be modularized Food and Drug Administration (FDA) with interim regu- and reused across a centrally managed content reposi- latory procedures intended to expedite the development tory, has emerged as a tool which provides a potential and review of new drugs to address unmet medical needs solution to target many of the efficiency challenges for in treating serious or life-threatening conditions (21 CFR CMC documents that persist during regulatory submis- 312) [18]. Since then, the FDA has adopted five programs: sion and review processes [7, 12]. While there is pres- Fast Track Designation, Breakthrough Therapy Designa - ently an abundance of cautionary thinking within the tion (BTD), Accelerated Approval, Priority Review, and pharmaceutical and biopharmaceutical industry with Regenerative Medicine Advanced Therapy (RMAT) [19]. regard to investment in novel information manage- Both BTD and RMAT are intended for drugs treating ment technologies, the value of SCDM and Pharma 4.0 serious or life-threatening illnesses and provide spon- enabling approaches will continue to increase as digital sors with similar advantages, with BTD regulated by industrialization continues and demonstrates the utility the Center for Drug Evaluation and Research (CDER) of rapid information sharing as a tool for increasing effi - and RMAT by the Center for Biologics Evaluation and ciency in regulatory submissions [13, 14]. Additionally, Research (CBER). In 2021, CBER approved three thera- resistance to leverage twenty-first century technologies peutics with the RMAT designation pathway and CDER hinges on our industry being highly regulated. However, approved 14 through BTD [20, 21]. the banking industry is also highly regulated, yet most In 2018, the FDA’s Oncology Center of Excellence global monetary transactions utilize similar technologies. (OCE) initiated Real-Time Oncology Review (RTOR) to B eierle et al. AAPS Open (2023) 9:11 Page 3 of 19 streamline the review process and further facilitate the treats a serious disease and/or shows clinical usefulness availability of groundbreaking therapeutics to patients by meeting an unmet medical need or shows improved with life-threatening conditions [22, 23]. With RTOR, efficacy and safety compared to current options. Condi - the sponsor and regulators carefully plan and agree tional early approval (CEA) applies to drugs where it is on a strategy and timeline for the rolling submission of difficult to provide confirmatory trials or doing so would module components. Although the Prescription Drug be too time consuming and the MA can be filed with User Fee Act (PDUFA) review clock does not officially adequate levels of efficacy and safety during exploratory begin until the last document is submitted, by supplying trials. Confirmatory clinical trial data must be submit - selected sections earlier, applications can sometimes be ted post-approval. The Sakigake designation is aimed at approved 3 to 4 months before the PDUFA goal date [24]. drug products targeting unmet medical needs, or for the The European Medicines Agency (EMA) has also treatment of serious or life-threatening conditions, and implemented several regulatory procedures designed to pairs the sponsor with a PMDA staff review concierge to expedite patient access to new medicines, including Con- streamline communication throughout the development ditional Marketing Authorization (CMA), Exceptional and application process. Sponsors also benefit from roll - Circumstances for rare diseases, Accelerated Assess- ing reviews, a shortened review period, and the ability to ment, Priority Medicines (PRIME) and Compassionate provide submission materials in English. During the first Use [25–29]. A common feature for eligibility for these 5 years, 37 drugs received this designation, and 10 were pathways is an “unmet medical need.” Certain pathways approved [35, 36]. like CMA also apply to orphan drug medicines which Several international collaborative review initiatives treat rare diseases (defined as those with a prevalence across regulatory agencies have been initiated to allow of 5 in 10,000 or less). However, the understanding of faster patient access to critical medicines, globally. Pro- “unmet medical need” in the EU, where there is no formal ject Orbis and the Access Consortium are two exam- definition, is very different from that laid out by the FDA ples of collaboration amongst regulators that have been [30]. Most of these pathways allow for the deferred sub- operating for several years. Project Orbis was initiated mission of certain information as post-approval commit- in May 2019 by the FDA’s OCE to leverage the scientific ments such as phase III clinical data, long-term stability and regulatory knowledge across participating countries data, and other data to refine the product manufacturing to enable faster global access to crucial cancer treatments control strategy. Each pathway follows its own timeframe [22, 37]. Review efficiency is improved through resource and expedites the review and approval to varying extents. sharing (e.g., by sharing reviews between the participat- Of the available expedited approval pathways, only CMA ing regulatory agencies). As of August 2022, eight coun- and PRIME are potential options outside the scope of an tries take part in Project Orbis: Australia, Brazil, Canada, emergency. In 2021, the EMA approved 13 drugs with Israel, Singapore, Switzerland, the United Kingdom (UK) CMA and six with PRIME designation [31]. and the US. In 2021, the FDA approved 26 marketing During the COVID-19 public health emergency, the applications supported by Project Orbis [38]. The Access heightened need for vaccines and/or therapies resulted Consortium, established in 2007, is a collaborative effort in the EMA allowing for a “rolling review” mechanism between regulatory agencies in Australia, Canada, Sin- under the “EMA plan for emerging health threats” [32, gapore, Switzerland, and the UK, that would benefit 33]. With this review mechanism, the EMA and the from work-sharing, enhancing synergy, and increased sponsors preemptively agree to a series of rolling reviews efficiency by reducing duplication [39, 40]. In addition, with predefined document submission timelines. This sponsors have the advantage of receiving consolidated allows documents to be submitted and reviewed as data questions from multiple markets, predictable timelines become available. Once the application package is con- for information requests (IR), and potentially, near- sidered sufficiently complete, the sponsor can proceed to simultaneous approvals in multiple markets. apply for CMA. As with other CMAs, additional data can The International Coalition of Medicines Regulatory be submitted post-approval. This process enabled a faster Authorities (ICMRA) is a voluntary organization com- review of COVID-19 vaccines to meet the public health prised of 24 member regulatory agencies and 15 associate emergency. member agencies. Together, they work to identify areas of Japan’s Pharmaceutical and Medical Device Agency potential synergies and leverage existing resources when- (PMDA) has three main pathways available for expedited ever possible [41]. At the start of the COVID-19 pan- review of a marketing application (MA): priority review, demic, the ICMRA issued a statement of collaboration. conditional early approval, and Sakigake [34]. Prior- This led to a large regulator-industry workshop in July ity review shortens the review time from 12 months to 2021 which was well-attended and had broad outreach 9 months. The criteria for this pathway are that the drug [42, 43]. From these discussions, the framework for two Beierle et al. AAPS Open (2023) 9:11 Page 4 of 19 collaborative pilot programs was developed: one for facil- of multiple presentations at risk and may require ity inspections, and the other for the assessment of CMC additional clinical stage amendments to support the post-approval changes. The two pilot programs began selected presentation intended for commercializa- accepting applications in June 2022 and are both under tion. Furthermore, the transition to commercialization oversight by the ICMRA working group for pharmaceuti- may include changes to the manufacturing site and/or cal quality knowledge management systems [39, 44]. The scale to meet projected demand for the product, which primary goal is to explore the feasibility of collaboration in part explains why data to support process valida- for facility inspections and increased harmonization of tion and product stability are on the critical path for data expectations for CMC post-approval submissions, the target submission date. These effects of accelera- both efforts that can be supported by improved manag - tion can result in limited commercial product supply ing of source data. at time of product launch onto the market, increasing the complexity of the CMC strategy and the number of CMC challenges in regulatory submissions post-approval changes, and thereby increased regula- of products under accelerated development tory submissions. Clearly, management of accelerated Based on a benefit-risk assessment, many acceler- global filings is complex and requires careful track- ated procedures outlined in the previous section allow ing of various data requirements which increase as a phase 2 data that shows clear indication of efficacy product progresses through development, expands to to be used as the pivotal clinical data for submission include submissions in multiple countries, and man- with phase 3 confirmatory studies to be started dur- ages responses to health authority questions along ing the MA review cycle for completion post-approval with post-approval changes and commitments (Fig. 1). [45]. However, accelerated clinical development poses This is a highly resource-intensive process that can major product development challenges by compress- be protracted for some years and is further delayed ing essential CMC activities into shortened clinical by reliance on archaic filing mechanics to relay CMC timelines, thereby potentially placing the required data. Therefore, efficiency gains in the processes that CMC data on the critical path for marketing authori- govern a filing strategy are of critical importance. zation submission [4–6, 46]. Optimal dose selection is These complexities in managing the submission often pending at the time of first subject dosing in crit- planning can be addressed in part by robust yet flex- ical registrational trials. This forces the development ible knowledge management which may be afforded Fig. 1 Compounding submission volume and complexity during development. The quantity of dossiers, country variants, information requests, and manufacturing changes substantially increases over time. For accelerated programs, later stages of development are often characterized by overlapping milestones and filing expectations, wherein the phase 3 trial may overlap with the filing of the marketing application. The marketing application may be filed in multiple discrete “waves” including groupings of different regions, wherein authoring, review, and approval timelines may overlap B eierle et al. AAPS Open (2023) 9:11 Page 5 of 19 by SCDM that works directly with content and data Current applications of SCDM rather than documents. Ultimately, in the current non- in the pharmaceutical industry digital document-based submission paradigm, incor- In addition to targeted CMC acceleration tools and poration of critical CMC data into the filing requires expedited regulatory pathways, Information Technology significant time and resources for authoring, data veri- (IT) infrastructure can be effectively leveraged to man - fication, formatting, and publishing, all of which nega- age resource demands and complex filing scenarios for tively compete with the expedited clinical timeline. To industry and global health authorities. While individual minimize the timeframe for preparation of CMC infor- organizations may pursue a multi-pronged approach to mation, innovative approaches and tools are needed IT modernization that consists of various elements of that facilitate efficient management of CMC data in Pharma 4.0, such as AI and machine learning, SCDM regulatory submissions. is of particular importance for enhancing data manage- Health authorities and industry pharmaceutical trade ment capabilities to support regulatory filings. SCDM is a organizations have recently discussed tools to support component-based approach to information management CMC acceleration. Along with existing submission that can drive regulatory modernization and provide strategies such as rolling reviews and negotiations on solutions for efficiency challenges faced by sponsors and uses of the established term “prior knowledge,” several regulators. SCDM can incorporate structured and semi- new ideas were introduced and considered during the structured data, wherein structured data is largely tabular COVID-19 emergency and may potentially be carried and in a highly ordered sequence which typically ascribes over to expedite product development outside of emer- to a controlled terminology list. Semi-structured data gency circumstances. Under PRIME, the EMA released retains a partial hierarchal format but allows for flexibil - a valuable toolbox for CMC acceleration that was avail- ity through input of free text.  Conversely, unstructured able in a draft form through 2021 and was published data is free text that contains terms that provide essential in 2022 [47]. Likewise, FDA released a new Manual information, typically in paragraph format (Fig. 2). of Policies and Procedures (MAPP) titled “Quality SCDM is based on the concept of a centralized and Assessment for Products in Expedited Programs” and interoperable data repository or library that is comprised plans to start the CMC Development and Readiness of modular content authoring blocks and data elements Pilot (CDRP) in 2023 to accelerate CMC development that build upon each other to create a product-specific for Investigational New Drug (IND) sponsors at both record. Using this concept, a content block can be defined CBER and CDER [48–50]. as a container for a stack of data elements, wherein the In addition to the regulatory tools and strategic data elements relate to one another and commonly methodologies described above, utilization of technol- appear together to comprise a data set or description of ogy to streamline the data management, authoring, a specific attribute (Fig.  3). SCDM leverages the reusabil- and verification of CMC information presents a com - ity of content from a given content block to build related prehensive approach for alleviating the impact of pre- content blocks or to facilitate reuse of the same content sent acceleration challenges. Capabilities  like SCDM block across applications, thereby drastically limiting the provide enhanced functionality in comparison to con- need for consecutive authoring, reviewing, and approval ventional submission preparation processes, aiming to cycles of the same content block or data element [7]. Data improve efficiency while simultaneously promoting a elements or content blocks can be distributed across science and risk-based assessment by reducing the time multiple electronic common technical document (eCTD) between digital data generation and data availability in sections for various regulatory filing requirements and the filing for health authority review [46]. SCDM could can be efficiently updated throughout the product lifecy - also support optimization of reviewing procedures cle. This interoperability can ease the burden of repetitive for health authorities through sharing of information authoring and allow for the auto-population of content, across applications or through a cloud-based system. which can be updated in real-time as changes or new Above all, the value of SCDM would be most evident data are applied. The narrative can be refreshed accord - for sponsors simultaneously managing multiple expe- ingly with author input as necessary. Eliminating data dited submissions worldwide, with responses to health verification alone with the use of a validated SCDM sys - authority questions and subsequent post-approval vari- tem significantly reduces review time and resources, as ations needed to optimize the manufacturing process there is no manual data transcription. As module 3 of over time [4–6]. The ability to repurpose prior knowl - the eCTD is comprised of designated datasets and ref- edge and other product filing data libraries rapidly for erenced details that are repeated across multiple nodes numerous submissions would provide an enormous (or CTD sections) in an unstructured format, regulatory gain in efficiency [47, 51–53]. dossiers become increasingly cumbersome to maintain Beierle et al. AAPS Open (2023) 9:11 Page 6 of 19 Fig. 2 Data formatting conventions for regulatory information. Sample stability data illustrating unstructured, semi-structured, and structured data formats are depicted. Key content and data input fields are highlighted in gray for visualization. While unstructured data characterizes much of the current format, SCDM principles are optimally applied to semi-structured or structured data. While data appearing in a structured table appears simplified, the raw data is still accessible via a variety of viewing formats. While not inclusive of all possible interfaces and navigation options, an example shown here utilizes “hover text” that shows the corresponding data value when the “conforms to criteria” field is highlighted Fig. 3 Structured content and data library for stability data. An overview of a structured content and data library housing stability information is depicted. Each black box constitutes a “content block” that is attributed to a specific lot. Inside each content block, information such as test method, acceptance criteria, and timepoints are accessible. Data is imported into the library directly from the data source (ex. LIMS, eLN). Over time, as development progresses, stability data continually accumulates across lots and, additionally, new lots are developed as the manufacturing process is optimized. Content blocks data elements are updated in real time as new data points become available from data sources. Content blocks and data elements can be “pulled” from the library to auto-populate module 3 CTD sections to prepare for submission B eierle et al. AAPS Open (2023) 9:11 Page 7 of 19 and continually update, particularly in the post-approval Similarly, SCDM can bring data from multiple man- environment wherein there can be multiple variations or agement systems together and allow for data intercon- supplements in preparation simultaneously. With SCDM, nectivity across systems through integrations. Currently, the individual content blocks can be structured, mapped data are stored and managed across multiple internal to different eCTD nodes where they are needed, and systems, such as Laboratory Information Management linked to a centralized data element repository for stor- Systems (LIMS), Electronic Lab Notebooks (eLN), Prod- age and maintenance, enabling an easier authoring pro- uct Lifecycle Management (PLM) software, and company cess and enhancing automation [12]. Instead of editing, data lakes. This makes it difficult to transfer, assimilate, data verifying, and republishing a full document, modifi - and track source data in preparation for regulatory sub- cations can be made to individual components as needed, missions. SCDM can be leveraged to build connectivity which will then auto-update in each section in which the between systems by structuring and contextualizing con- components appear. In this way, changes can be applied tent. The structured content and data library can ulti - across multiple sections and multiple regions simulta- mately be used in combination with an enterprise data neously. From a technical perspective, SCDM can facili- lake (EDL) to achieve a unified CMC data model that tate parallel review activities across different agencies establishes semantic context between data elements and by helping to manage multiple country-specific varia - is fully interoperable across systems and applications tions that impact the same CTD section, such as speci- [12]. fication sections, which may be different across regions The use of SCDM in a regulatory and pharmaceuti - due to individual agency regulatory requirements and cal context is in its relative infancy with comparatively preferences. An additional compelling advantage to hav- little real-world experience versus traditional operat- ing such a centralized data repository is to support the ing models for submission assembly. Biopharmaceuti- acquisition and integration of a program/company, where cal companies, as well as global health authorities, have the new sponsor company is responsible for retrieving begun to preliminarily explore SCDM-based architec- archived data to support new submissions at various ture and solutions internally within recent years as part points in the product lifecycle, often in the absence of the of a larger shift towards regulatory modernization and technical development experts. digital system expansion, but it is not yet a widespread In addition to supporting efficiency by optimizing industry standard or regulatory expectation [7]. Several how content is authored, managed, and reused, SCDM other industries with their own sets of complex regula- can also enable digitalization by decoupling CMC data tions have demonstrated successful use cases digitization, from discrete documents, to move towards a data-driven including banking and financial services, the food and approach. As discussed previously, structured content beverage industry, automotive industry, marketing, and using a re-usable structured content and data library can aerospace, which showcases the suitability of structured house modular blocks of information (data with meta- content across complex, regulated environments [56–61]. data tags) to be used internally to build the content of There is increasing support towards implement - an on-demand internal data report, as well as externally ing structured content-based solutions in life sciences to address a health agency data request [12, 54]. For and pharmaceutical organizations which is demon- example, in FDA submissions, a drug master file (DMF) strated, in part, by the emergence of commercial tools is a current mechanism for reusing data, which can be offered by software and data management support ven - replaced with SCDM for future applications. This “data dors for SCDM solutions tailored for biopharmaceuti- on demand” SCDM approach can be considered a tech- cal use cases. Over the past 5 years, as companies have nologically advanced version of the DMF mechanism. adopted SCDM approaches internally, technological The DMF can be updated and maintained routinely in solution developers have evolved alongside the industry, an automated manner independently from a given filing as many vendors now showcase customer testimonials or application. For example, stability data stored in the and successful case studies from across multiple domains cloud for different drug product CTDs can be directly of biopharmaceutical companies, including research pulled for a new submission using SCDM. In a similar and development, regulatory, labeling, and operations. manner as using data from the DMF, SCDM can share Select examples of platform-based applications devel- submissions and data in a digital format in the cloud. oped to support the management of CMC regulatory Easy digital access to data used in amendments, varia- data include Docuvera’s CMC solution, which provides tions, annual reports, and supplements can be repur- a single-source authoring system for reviewing, approv- posed in specific areas of a submission for use globally ing, publishing, reusing, and managing CMC content; ® ™ depending on agency requests [55]. Cognition’s Lighthouse system, which can generate automated structured stability data reports from data Beierle et al. AAPS Open (2023) 9:11 Page 8 of 19 imported manually or from source systems of record; content and structural requirements, they lack the level and QbDVision , which has a suite of content manage- of section-by-section detail and granularity that would ment solutions for organizing and reusing CMC data be needed to support a fully structured application. The throughout the product lifecycle [62–64].  Other solu- lack of data standardization leads to the increasing het- ® ® ™ tion providers, such as Cognizant, IQVIA, OpenText , erogeneity of submissions across sponsors and regula- Esko, InteliNotion, and Vasont , have created SCDM tors, as sponsors may submit data in multiple formats tools specifically for life science and biopharmaceutical while regulators at different agencies may use different information management, which can be applied across tools and metrics for assessment. Differences in syntax domains, including CMC [56–59]. Vendors such as Veeva and nomenclature can make it difficult to map pieces of and LORENZ are creating specific toolsets to help organ - information that are conceptually identical. For exam- ize structured data in line with upcoming regulatory ple, the pharmaceutical dosage form categories “cap- data requirements [65, 66]. Additionally, companies may sule, hard” and “hard capsule” are definitionally the same develop in-house applications using commercially avail- and ontologically should be modeled as the same object able data visualization programming packages (e.g., R (thing). Similarly, a release specification result for a criti - Shiny) that are specifically customized to integrate with cal quality attribute may be operationally identical to the existing business data architecture and deliver structured stability time zero result for that attribute and should be content solutions [67]. The availability of configurable modeled for both purposes. However, if this mapping is commercial software and Software as a Service (SaaS) not properly conducted or completed, these items could platform solutions increases the accessibility of SCDM be rendered as separate objects and create limitations for wider implementation across biopharmaceutical for machine-based assessment and content auto-popula- companies with differing organizational sizes, technolog - tion. Ultimately, these differences in terminology across ical capabilities, and data complexity. regions create unneeded complexity that contributes to variations in data interpretation. Emerging regulatory enablers of SCDM The International Organization for Standardization While adoption of SCDM solutions can support effi - (ISO) originally published the Identification of Medici - ciency and optimization of resource management, par- nal Product (IDMP) standards in 2012 with the objec- ticularly in accelerated filing scenarios, there is presently tive of enabling simplicity and consistency of medicinal no requirement, or significant external impetus, for biop - product and substance data that are exchanged between harmaceutical developers to pursue these advancements sponsors and regulators [68]. IDMP standards span mul- in technology as dossiers can be compiled and organized tiple different domains in the pharmaceutical industry manually using current operating procedures. However, in a limited scope, including product labeling, safety, as the industry collectively advances towards digital pharmacovigilance, and CMC, focusing on the elements maturity as part of Pharma 4.0, the need to reconfigure that are deemed most essential for medicinal product from unstructured to structured data management solu- and substance identification. Specific coverage areas tions will be further escalated by key imminent develop- include product and substance nomenclature, manufac- ments that are gaining momentum globally with several turers, characteristics, marketing authorization status, health authorities. and packaging details. Several regulators, including the EMA, have communicated their intentions to require Emerging submission requirements for structured, compliance with ISO IDMP standards, but formal guid- standardized CMC and quality data ance towards implementation is pending across multiple Data standardization is a key driver for automation and regions. represents an important step towards structuring data by Specifically, the EMA plans to implement ISO/IDMP enabling consistency and interoperability. Presently, there compliance by utilizing an approach based on the four are no data standardization requirements for CMC data domains of data within pharmaceutical regulatory pro- that are submitted to regulatory authorities. While spon- cesses including Substance, Product, Organization and sors must meet the requirements outlined in local leg- Referentials (SPOR). EMA’s efforts intend to facilitate islation and are advised to follow relevant International the reliable exchange of key medicinal product infor- Council for Harmonization of Technical Requirements mation in a structured, standardized, consistent, and for Pharmaceuticals for Human Use (ICH) guidance and efficient manner in line with the healthcare industry regional and country-level guidance, there are no data [69]. While the implementation timeline for SPOR standards currently in use that govern how data are pre- is to be determined, the EMA is expected to initiate sented, formatted, and structured in the regulatory dos- the implementation of IDMP standards through the sier. Although ICH M4Q guidelines provide baseline related Digital Application Dataset Integration (DADI) B eierle et al. AAPS Open (2023) 9:11 Page 9 of 19 Adoption of data analytics tools to support regulatory project, which will replace the current PDF-based review electronic Application Form (eAF) with a web-enabled In 2018, the FDA first shared its plans to create a risk- form [70]. based, computer-aided reviewing tool entitled Knowl- Separate from SPOR, the FDA has developed an edge-Aided Assessment and Structured Application alternative data standardization initiative, focus- (KASA) [81]. The KASA tool would input received struc - ing specifically on CMC data requirements under tured data into an analytical database that utilizes risk the Pharmaceutical Quality/Chemistry, Manufactur- assessment algorithms to evaluate key CMC and quality ing, and Controls (PQ/CMC) project that expands attributes, such as manufacturing facilities, pharmaceu- the IDMP concept across CMC. The initiative aims to tical development, and control strategy [82]. The KASA enable sponsors to pivot toward providing structured tool is intended to address inefficiencies in the review data applications to improve interoperability between process, promote consistency and objectivity during stakeholders and increase the efficiency of the FDA’s analysis, and keep pace with technological innovation in review of CMC data. As part of the 2012 Food and Drug line with the goals of the Pharmaceutical Quality for the Administration Safety and Innovation Act (FDASIA), 21st Century Initiative [76]. The FDA’s related PQ/CMC the FDA released an initial Federal Register Notice in initiative would support implementation of KASA by 2017 on a series of structured data elements intended enabling sponsors to provide structured data in an appro- to provide structure across a variety of CTD mod- priate format at the time of regulatory submission, which ule 3 sections, including stability, specification, ana - could then be directly imported into the KASA tool for lytical methods, and batch analyses [71]. In 2022, the analysis. Both initiatives represent a change in thinking FDA shared a refined and expanded version of the PQ/ towards an objective data-driven, risk-based decision- CMC data elements including mapping to Health Level making approach wherein unstructured narrative is 7 (HL7) Fast Healthcare Interoperability Resources minimized in favor of usable, assessment-ready data. The (FHIR) [72, 73]. initial scope to pilot the KASA tool included Abbreviated The FDA’s PQ/CMC standards as well as the EMA’s New Drug Applications (ANDA) for generic drugs, as SPOR rely on exchange specifications to enable the this represents both a high-volume area for FDA review- transfer of information from sponsors to health author- ers and a high-impact area for consumers. The solution ities. Both standards utilize FHIR as an exchange stand- is anticipated to evolve over the next 5 years to include ard. HL7 FHIR is an open-source data format with an a review of New Drug Applications (NDAs), Biologics accompanying application programming interface License Applications (BLAs), and post-approval changes (API) that leverages flexible and modifiable resource [76–79]. elements to bring structure and standardization to healthcare information while allowing for targeted cus- Innovations in cloud‑based technology tomization [74]. Through FHIR, sponsors and health Cloud-based computing harnesses the collective power authorities will be able to securely exchange elec- of numerous interconnected servers to enable a custom- tronic correspondence through FHIR messages, which izable suite of computing and processing capabilities, can include a bundle of structured information that is including analytical tools, software applications, remote downloadable in a variety of formats including XML data storage, and access to volumes of information on- and JSON. FHIR can accommodate regional variations demand via the intranet/internet. Flexibility, scalability, in terminology lists, which supports its use as a flexible, and interoperability are among the key value propositions global solution for standardization [75–79]. for cloud services, which allow systems within the cloud- In addition to FDA’s and EMA’s efforts to develop based ecosystem to communicate with one another, FHIR-compliant data standards, a new HL7 FHIR pro- bringing data from different sources together to achieve ject was established in late 2022 with the goal of devel- new levels of accessibility. For pharmaceutical companies oping global internal data standards to enable exchange and regulators, the practicality of SCDM can be further of data across biopharmaceutical industry data systems. augmented by a cloud-enabled unified data model that These standards are being developed in collaboration connects data to allow for the seamless access and use of with industry stakeholders and will maintain alignment data [12]. with both PQ/CMC and ISO IDMP to the extent fea- Regulators are increasingly moving towards cloud- sible. The project, entitled, “Data Exchange Industry – based systems to optimize processes such as data Pharmaceutical Quality (dx-PQ)” will cover a variety of exchange, assessment, and archiving. In the US, as scenarios in its initial iteration, including technology part of the FDA’s Technology Modernization Action transfers, manufacturing process changes, and stability Plan (TMAP), the agency is exploring next steps and data updates [80]. Beierle et al. AAPS Open (2023) 9:11 Page 10 of 19 requirements for migrating the FDA’s IT infrastruc- secure workspaces that will be made broadly accessi- ture to a cloud-enabled model. As reported in the 2022 ble by all life science companies and health authorities TMAP Anniversary Report, 35% of the agency’s systems around the globe. The long-term vision of the platform is are utilizing cloud-based approaches, which has contrib- to decrease regulatory submission and review timelines, uted to significant resource savings and assisted with the as well as development costs, to accelerate availability of development of scalable next-generation data centers medicines for patients. As an integral aspect of the vision [83]. Similarly, in the EU, the EMA has shared its intent to establish a cloud-based data exchange platform, the to migrate its IT systems entirely to the cloud by 2025 Accumulus platform aims to support and aid adoption to allow the agency to further modernize and digitize its of the aforementioned CMC data standards currently in operations [84]. To date, many of the externally facing development through a flexible and accessible user inter - systems used by the EMA have already adopted a cloud- face and structured data repository. Notably, Accumu- enabled infrastructure, such as the EMA’s IRIS platform, lus Synergy is a primary stakeholder in the development which can be utilized to initiate a number of regulatory of the HL7 industry internal CMC data standard, Data procedures such as applying for orphan drug designation, Exchange Industry – Pharmaceutical Quality (dx-PQ) seeking scientific advice, and providing updates on mar - [80]. keting authorization status for products [44, 85]. While it is important for regulators to upgrade and Applying the principles of SCDM modernize their own internal systems to promote con- through the product lifecycle regulatory process: tinuous technological innovation and advancement, a case study regulators and sponsor companies would benefit from In this section, a hypothetical case study is presented as having a common, international, cloud-based informa- an example of how SCDM can be leveraged to increase tion exchange platform to conduct correspondence and efficiency in CMC submissions for a medicinal product initiate regulatory procedures. In 2020, Accumulus Syn- in an accelerated development scenario. Figure  4 illus- ergy, a nonprofit organization and technical solution trates the high-level development timeline demonstrating innovator, was formed in response to this growing need. this example product. Early MA submissions (“wave 1”) Accumulus Synergy is creating a cloud-enabled solution are planned on the basis of compelling phase 2 clinical that fosters collaboration between and across regula- data. As a result, the clinical trial application (CTA) sub- tors and industry, enables real-time regulatory submis- missions supporting confirmatory phase 3 studies may sion, and allows for dynamic structured data exchange be ongoing at the same time, resulting in overlapping for CMC and other domains [86]. With support from workload and adding to project management challenges. 12 biopharmaceutical sponsors, Accumulus is develop- The timing of necessary changes to the manufacturing ing a scalable, democratized platform with shared and process, product formulation, strength, and container Fig. 4 Case study summary timeline. The timeline outlines the major regulatory filing milestones for the hypothetical case study. Each filing activity milestone is able to leverage substantial content and data reuse supported by the structured content and data library to streamline authoring and submission B eierle et al. AAPS Open (2023) 9:11 Page 11 of 19 closure system or site must be carefully considered in to the overall program timeline. SCDM better supports order to ensure uninterrupted supply to patients glob- incorporation of any CMC updates that are needed dur- ally. Due to the compressed timelines, certain elements of ing this delay since these are captured within the content product optimization as well as many necessary changes library via content blocks and data elements. These ele - may need to be deferred to the post-approval stage, at the ments can be readily deployed to relevant parts of the same time as filing of the “wave 2” MAs. regulatory applications concurrently for all countries. The product is identified in pre-clinical development The advantage of SCDM in this scenario is agility through as a potential target for undergoing accelerated develop- rapid incorporation of updated CMC information in sub- ment. Leveraging SCDM technologies, discovery, and missions, in response to clinical timeline changes as they preclinical data are appropriately logged and catego- occur in real-time. rized in a cloud-based EDL and structured content and When compelling phase 2 clinical results are received, data library where data are centrally stored, organized, applications are made to gain expedited regulatory path- and made accessible for future component content use. way designations (BTD in the US, PRIME designation Before first-in-human (FIH) studies can take place, the in the EU, and Sakigake in Japan). Further complexities regulatory team initiates the process of drafting CTAs to are evident if an expedited review designation is received support initial studies, focusing on inaugural target mar- in one market and not in others, resulting in staggered kets. The team accesses the data content from pre-clini - submission planning and constantly shifting scenarios. cal studies in the EDL and structured content library to Unanticipated early approvals also may necessitate accel- map relevant component content blocks to each respec- eration of scale-up and site transfer activities to meet tive CTA filing. This process enables a direct digital con - ongoing clinical trial supply demand and commercial nection between material used in preclinical and early requirements for each of the multiple countries targeted clinical studies, which has historically been challenging for wave 1 MA submissions. The team is also simultane - as it spans many years and personnel changes. Continual ously managing CTA submissions for multiple confirma - data collection from these early process development tory phase 3 clinical trials to support additional data experiments is enabled by tagging and mapping informa- collection across regions. As shown in Fig.  1, this repre- tion that can populate product and region-specific con - sents an intense period of overlapping submissions and tent blocks in a data library. These content blocks contain responses to health authority requests for information for all the CMC information that can be built sequentially both CTAs and MAs. Participation in collaborative regu- as the product development program matures, as shown latory efforts such as Project Orbis requires further coor - in Fig.  3. Following any required updates due to agency dination and handling of multiple simultaneous requests questions from the initial CTA applications, content for information, often with short turnaround times as blocks can be re-used for streamlined file-building and well as country-specific CMC summaries such as quality submission operations in subsequent CTA filings, in assessment aids required by regulators. line with the global regulatory strategy. As opposed to Without SCDM, the MAs would be prepared follow- authoring documents specific to each filing, the product ing current practices, in which a core CMC dossier is first data are accessible and reusable via a multi-dimensional created from data sources with aggregate information data network of semantically connected data elements requirements for all countries. From this global dossier, throughout the product lifecycle. In lieu of tracking down the team would need to prepare multiple country-spe- and aligning documents with specific phases of develop - cific MAs and ongoing CTAs. Since this team does have ment and regions, data elements of the content record an established SCDM workflow, they do not need to can be flexibly deployed to the required filings from a manually generate the different documents and variants. core content repository. This agility is especially valuable The tagged data in the content block is retrieved from given the shifting timelines that are often associated with the EDL and structured content library and loaded into accelerated development. the relevant sections of the application. Thus, data can As clinical studies progress, alignment between the travel from a centralized EDL that is comprised of a con- clinical and CMC activities must be continually evaluated solidation layer (that accrues relevant product data from and maintained, as changes to clinical development mile- various data sources) and a semantic layer (that connects stones may substantially impact CMC resource alloca- the product data elements based on an ontological data tion and timelines. For example, if late-breaking clinical model which defines the relationships, classifications, results were to suggest that the product delivers substan- and associations of data elements in a cloud-based eco- tial benefit in a subset of the patient population with a system) (Fig. 5). specific genetic mutation, development of a companion Most of the health authorities in this hypothetical diagnostic would be required which might cause delays case study accept MA submissions in eCTD format, but Beierle et al. AAPS Open (2023) 9:11 Page 12 of 19 Fig. 5 Comparison of regulatory submission processes with and without SCDM. A comparison of regulatory CMC submission assembly and dispatch is shown. Without SCDM, data is manually transcribed from the source into a technical report. The technical report is then used as a source document for a regulatory document, of which there are multiple regional variants created manually. Compilations of documents are then sent individually to health authorities for review, requiring the company to maintain multiple regional dossier variants. With SCDM, manual authoring steps can be reduced or eliminated as content and data can be taken directly from the source system, processed and semantically mapped via an enterprise data lake, and made available for incorporation in a regulatory filing via the structured content and data library, which is made up of content blocks. The content blocks can be reorganized, updated, and customized according to regulatory objectives and regional filing needs. The structured content and data library can achieve flexible output options, including electronic data submission, cloud-based information transfer, and printable paper-based filings some have the appropriate IT infrastructure to accept changes to include in the MAs or in post-approval fil - data in FHIR exchange format. SCDM tools enable the ings. The team files its MA first in one jurisdiction; At same datasets to be reused across a variety of outputs this time, two manufacturing sites A and B are included and file types, including paper, PDF, and FHIR-based but plans for a third site C are underway to meet pro- data submissions. SCDM ultimately provides a hierarchy jected demand. By the time the team files the MA in of inherent structure defined by semantic relationships additional jurisdictions, the final wave 1 countries, all between pieces of data which can be represented across sites are operational and thus included in the MA. The file formats and presentations. This flexibility is a key team can leverage SCDM to update the regional MAs aspect of SCDM’s utilization as it can accommodate var- in real-time based on manufacturing site readiness and ying levels of technological maturity across global regu- data availability. lators to simultaneously produce traditional (paper, PDF) After the wave 1 MA submissions, several hundred and data-driven submissions. SCDM would additionally information requests (IRs) are received from multi- streamline the MA process by ensuring that country-spe- ple agencies. It is advantageous for the sponsor to have cific summaries required by regulators can be completed traceable country-specific data to quickly and accurately accurately and expeditiously. provide a response to the agency requests given the time As the team is preparing the initial MAs for submis- constraints for IRs imposed by the various agency regu- sion, advancements in process development and manu- latory frameworks. With SCDM, all this information facturing are occurring simultaneously. As mentioned is readily available, as data on stability, comparability, earlier, scale-ups and site transfers may be needed to and number of lots manufactured is mapped to specific meet commercial and clinical supply chain require- applications and regions for which they were included. ments, resulting in complex tracking of these changes Without SCDM, it would be difficult to track what infor - across MAs and CTAs. The team must decide which mation was included for which country. B eierle et al. AAPS Open (2023) 9:11 Page 13 of 19 The use of prior knowledge and SCDM can provide SCDM helps the team to manage which submissions are structured content blocks to leverage related stability required for specific countries and updates the informa - data from similar products for justification in rapid deci - tion needed. This results in a more seamless rollout of the sion making. Since the timeline is accelerated, limited new presentation in pre-filled syringes which improves stability data are available from lots that can be justi- patient adherence and outcome. fied as primary stability lots per ICH definitions [87]. Ultimately, throughout the MA filing process, author - The team leverages prior knowledge from representative ing and submission timelines could be reduced by as products to refine the shelf-life analysis and model the much as 50% using SCDM in comparison to the tradi- stability profile for the candidate product. Additionally, tional process. Additional savings can be realized by ena- the use of SCDM enables updates to stability data simul- bling  faster filings in subsequent markets, thus reducing taneously in different submissions as they become avail - initial MA approval times in wave 2 regions to 4-5 years able. At the time of the initial MA filing, the team has as compared to a current average of 7-10 years. 12 months of stability data for two lots and 9 months for the third lot. A shelf-life at approval of at least 18 months The evolution of CMC submissions is proposed, and this generally requires real time data Until the creation of the ICH CTD, physical copies of from at least 3 representative lots to be provided dur- regulatory applications with unharmonized format- ing review. The filing team queries through the product- ting were shipped on pallets to major market agencies specific records and identifies two commercial products as illustrated schematically in Fig.  6. The physical logis - with similar manufacturing processes, formulations, tics and paper reviews in preparations for shipping the and structural characteristics, but with slightly different application pallets were a massive hurdle for companies SKUs and packaging configurations. One of the commer - in an increasingly globalized marketplace. The CTD as a cial products has 18 months of stability data while the harmonized work product was a valuable advancement other has 36 months. The team provides these stability that created a structure for regulatory submissions that data to supplement and model the predicted expiry sup- would be recognized by ICH member jurisdictions [88]. porting justification for a reasonable shelf-life at original However, the medium by which information was shared approval. With the use of SCDM, the product team can continued to be a physical paper copy. As technology supply these data to aid the approval process and are later evolved, the eCTD emerged moving a physical paper able to update filings in real-time once product-specific copy into an electronic structure and format. The ICH testing is completed.  eCTD was first adopted in 2003 by the EMA [89]. This After the product is approved, it becomes necessary transition from physical to electronic paper has made it to carefully manage the post-approval changes in each easier for regulatory agencies to review the submissions country such as the addition of a new manufacturing site. by providing the ability to hyperlink to different locations As shown in Fig.  4, the team is preparing wave 2 MAs within the structure of the eCTD. Sponsors benefited while also submitting manufacturing site C informa- from reduced allocation of resources to the preparation, tion to many of the wave 1 countries as a post-approval storage, and shipping of physical documents. The process change. SCDM can help by centrally storing all the site- was a favorable and noteworthy transition as the industry specific information through data elements that can then entered the twenty-first century, providing value to spon - be picked up and utilized for any one of the submissions. sors and health authorities by harmonizing the global Lastly, by using SCDM, the product team more effec - regulatory submission process. The industry and health tively manages a post-approval change to the product authorities can provide significant benefit to patients by presentation in all countries. The product is initially accelerating the logistics of regulatory submissions and approved as a once-weekly subcutaneous injection that the review processes through the use of digital technolo- is transported in vials and administered for 6 months. gies and adoption of an easily searchable and verifiable The once-weekly course of administration is burden - data-centric approach that would be superior to the doc- some for patients who must arrange transportation to ument-based eCTD. their healthcare provider’s office. This burden negatively The next milestone will be a move to cloud-based impacts adherence to the dosing regimen. After wave 1 submission systems with the use of targeted SCDM MA approvals, the sponsor optimizes the delivery with a components. Directing structured, verified source data new administration regimen which requires one injection components into regulatory submissions will enable tran- every month and is shipped as a pre-filled syringe. To this scendence beyond the eCTD. The cloud-based structure end, MAs for wave 2 countries will contain this presen- will contain “open” shared and “closed” restricted areas tation mode but wave 1 MAs will need to be updated with portals to control access within and between these according to each country’s reporting requirements. areas. This will promote concurrent and collaborative Beierle et al. AAPS Open (2023) 9:11 Page 14 of 19 Fig. 6 Summary of past, present, and future regulatory filing processes. While physical, paper-based submissions were the standard operating model in the past, the current regulatory framework in many major markets supports electronic submission of regulatory information in eCTD format. The conversion to an electronic system has ushered in multiple benefits, but there are ways to improve. In the future, electronic filings can achieve standardization and interoperability across data systems via HL7 FHIR, which is adapted for a real-time, cloud-based exchange ecosystem regulatory submissions and reviews between the spon- biopharmaceutical industry is struggling to determine sor, agencies, and third-party collaborators, with a focus how best to use current technologies in a highly regu- on reporting of data as opposed to document creation. lated environment [12]. Today, regulatory success for the This future state requires sponsor and regulatory agency biopharmaceutical sector remains solely dependent on endorsed collaborative efforts equivalent to the global the exchange of electronic or physical documents, limit- developments of the CTD and eCTD. Data-centered ing communication with health authorities to “in series” submissions can potentially advance inter-agency prod- transactions as illustrated in Fig. 1. uct discussions and provide CMC improved surveillance Health authority initiatives like KASA, PQ/CMC, ISO/ methods by accessing Module 3 data on demand for IDMP (SPOR), and ICH M4Q(R2) have the opportunity agency-related questions and thus drive more efficient to lead the way toward digitalization and globally aligned regulatory oversight. structured regulatory filings [77, 90–92]. Although these As the biopharmaceutical industry gravitates towards initiatives are in their early stages, they are providing the patient centricity, both sponsors and regulators must vital foundation for a modernized regulatory filing sys - continue to work not only to protect the safety of the tem. Both PQ/CMC and ISO/IDMP (SPOR) initiatives patient population but must also focus on deliver- are FHIR-based and provide a common global language ing and maintaining supply of therapies to patients in a for sponsors and health authorities to leverage for the more timely and efficient manner. Numerous industries secure exchange of electronic information. The align - have already leveraged twenty-first century technologies ment of the described health authority initiatives with to enhance speed and productivity [12]. However, the FHIR data exchange and a cloud-based ecosystem would B eierle et al. AAPS Open (2023) 9:11 Page 15 of 19 revolutionize regulatory filings, transcend the current aiding in supporting efficient data collection and there - capabilities of the ICH eCTD, and move the biopharma- fore improving regulatory discussion and collaboration ceutical industry into a modern application architecture. through natural language processing and vision applied Despite its many demonstrated advantages, there are to regulatory intelligence. As an example, AI could be some challenges related to SCDM implementation and harnessed to address responses to agency questions by use of cloud-based platforms that revolve around data drafting a response from content within the data lake localization, management, access, privacy, and legality and based on previous responses. At the post-approval [93]. Regulatory agencies want to preserve their auton- stage, AI implementation can be used in the industry to omy and companies need to ensure their intellectual learn continuously about each product change and more property (IP) is safeguarded. Decisions as to whether accurately identify higher and lower change-associated data will be centralized and managed by a third party, risks to better match regulatory reporting requirements or a hybrid method will need to be made. Standards including documentation. AI could learn from simi- will need to be put in place regarding system interoper- lar agency requests or questions made previously for ability and cybersecurity to protect patient and IP data other products, evaluate similarity between those prod- from breaches. Application programming interface (API) ucts, and use those prior knowledge data to assess the specifications will need to be structured such that each risk presented by a given change. Understanding of risk player in the regulatory ecosystem is only sharing what could potentially lower the reporting category for that is necessary and internal information is secure and pro- change. AI can be used together with other tools to pro- tected. Moreover, the systems will need to be built with vide essential information to a health authority including global compatibility in consideration. Region-specific data and modeling to support the risk assessment and legal hurdles will also need to be identified before imple - to mitigate existing risks. From a regulator’s perspec- mentation. Legal considerations regarding dataset server tive, AI can enable iterative learning about a particular localization, submission archival, and electronic verifica - change relative to other changes related to a product or tions will need to be addressed. different products or across sponsors. Health authorities Another challenge that hinders SCDM implementa- would also be able to take each sponsor’s distinct quality tion is that the current system requires further standardi- systems into account. SCDM would then be able to facili- zation and structuring. At present, long, unstructured tate the gathering of all available knowledge to assess the narratives are commonly included in the CMC sections risk of a particular change more appropriately in a sys- of the eCTD. Although these are intended to be data- tematic manner and thus evaluate the critical aspects of driven sections, companies may share more informa- its impact. tion and supplementary analysis than is necessary, often motivated by a desire to avoid future inquiries. Discus- Conclusion sions will need to be had to provide clear standardized Adoption and utilization of expedited regulatory review guidelines on what is and is not essential in the regula- pathways are increasing on a global scale. While this sup- tory decision-making process. Such conversations can be ports the acceleration of product availability for patients supported by regulators’ interest in developing risk-based with unmet medical needs, there are many efficiency and review algorithms, such as KASA [79]. Shorter, auto-gen- resource challenges that must be mitigated in acceler- erated summaries can be used to replace extensive narra- ated development environments. Navigating the myriad tives where applicable. This will allow for more effective regulatory requirements and timelines requires strategic resource allocation to the reviewing of essential data as coordination. opposed to reviewing extraneous text creating a more It is possible to accelerate drug development and efficient and nimble submission and review process. advance treatments to patients faster if product data, In the future, AI pattern recognition could be har- and data from applicable prior knowledge from other nessed for strategic planning as well as to track patient molecules, is managed more efficiently through a SCDM safety. AI-based technology is being adopted for phar- approach. The current system locks data for each prod - macovigilance to help with adverse event intake pro- uct into PDF documents which are manually generated, cessing and could potentially be used to assist with the verified, reviewed, published, and submitted. Health decision-making process for safety correlations [94, 95]. authorities must in turn manually retrieve submitted data Additionally, AI would be useful in searching through locked in PDF documents to be analyzed and compiled data to identify patterns in agency requests for further into their systems. This is a laborious, inefficient, and information, establish precedent in regulatory decision error-prone process. Sourcing prior knowledge data from making, and help seek consistency in agency reviews separate product dossiers is a particular challenge for a [96]. AI in regulatory may begin streamlining work by document-based system. Employing SCDM would mean Beierle et al. AAPS Open (2023) 9:11 Page 16 of 19 FIH First in human that structured data blocks can be deployed to relevant FDA Food and Drug Administration sections of the eCTD and could even be employed across FDASIA Food and Drug Administration Safety and Innovation Act different product eCTD sections. This process would HL7 Health Level 7 IDMP Identification of Medicinal Product ensure data integrity and traceability, making it more IR Information request amenable to the use of tools like modeling. A stepwise IT Information technology approach to implementing SCDM in regulatory submis- ICMRA International Coalition of Medicines Regulatory Authorities ICH International Council for Harmonization of Technical Require- sions can be envisioned. ments for Pharmaceuticals for Human Use Sponsors, regulators, and patients all share the same ISO International Organization for Standardization goal: faster access to safe and effective treatments. IND Investigational new drug KASA Knowledge-Aided Assessment and Structured Application Towards this common goal, sponsors, health authori- LIMS Laboratory Information Management Systems ties, and third-party organizations need to work together MAPP Manual of Policies and Procedures to develop the infrastructure and supportive regulatory MA Marketing application NDA New Drug Application policies needed to enable the utilization of information OCE Oncology Center of Excellence technology to accelerate the preparation, submission, and OMS Organisation Management Services review of regulatory filings. The vision for an efficient and PQ/CMC Pharmaceutical Quality/Chemistry, Manufacturing, and Controls PDUFA Prescription Drug User Fee Act expedited regulatory submissions process is the use of PRIME Priority Medicines SCDM in single-sourced filings and collaborative agency PLM Product Lifecycle Management reviews, with manual submission tasks replaced by auto- PMDA P harmaceuticals and Medical Devices Agency PMS Product Management Services populated filings, assisted by system interoperability and RTOR Real-time Oncology Review API integration in a cloud-based exchange platform. A RMAT Regenerative Medicine Advanced Therapy cloud-based submission system with SCDM integra- SaaS Software as a Service SOP Standard Operating Procedure tion which allows sponsors to reuse information with- SPOR Substance, Product, Organization and Referentials out the need to generate PDF documents will provide a TMAP Technology Modernization Action Plan more seamless submission and lifecycle management UK United Kingdom US United States process. Health authorities will be empowered to make better decisions, based on data that is more traceable, Authors’ contributions reliable, and transparent. CMC data is used, updated, and All authors have contributed equally on writing, editing, and reviewing the manuscript submitted. All author(s) read and approved the final manuscript. reused hundreds if not thousands of times throughout a product’s lifecycle. Improved management of these data Declarations and its usability can propel therapeutic innovation into the future. It is up to sponsors and regulators to work Availability of data and materials together and build this new infrastructure that enables Not applicable. acceleration by eliminating underlying inefficiencies. It is Competing interests imperative that patient treatment should not be delayed Jill Beierle, Marquerita Algorri, Marisol Cortés, Nina S. Cauchon, Andrew because of outdated regulatory document preparation Lennard, J. Paul Kirwan, Shirley Oghamian, and Michael J. Abernathy reports financial support which was provided by Amgen Inc. and submission systems. Funding This research did not receive any specific grant from funding agencies in the Abbreviations public, commercial, or not-for-profit sectors. API Application programming interface AI Artificial intelligence Acknowledgements ANDA Abbreviated New Drug Application The authors would like to thank Gerd Kleemann, Gino Grampp, Jason H. BTD Breakthrough therapy designation Binder, Pablo Rolandi, Eric Jordan, and Nitin Rathore for their helpful sugges- CBER Center for Biologics Evaluation and Research tions throughout development of this manuscript. CDER C enter for Drug Evaluation and Research CMC Chemistry, Manufacturing, and Controls CDRP Chemistry, Manufacturing, and Controls Development and Readi- Received: 1 February 2023 Accepted: 27 March 2023 ness Pilot CTA Clinical trial application CTD Common technical document CEA Conditional early approval CMA Conditional marketing authorization References DADI Digital Application Dataset Integration 1. Berdel WE (2021) Unintended regulatory caused early death-a difficult eAF Electronic application form endpoint in cancer patient care and treatment. Cancers (Basel) 13(6):1457 eCTD Elec tronic common technical document 2. Friedersdorf C (2021) The death toll of delay. The Atlantic. Available from: ELN Electronic Lab Notebooks https:// www. theat lantic. com/ ideas/ archi ve/ 2021/ 08/ fda- delays- carry- EMA European Medicines Agency death- toll/ 619871/ FHIR Fast Healthcare Interoperability Resources B eierle et al. AAPS Open (2023) 9:11 Page 17 of 19 3. Helwick C (2015) Delays in drug approval are deadly, highlighting the need eering/ janua ry- febru ary- 2022/ toward- single- global- contr ol- strat egy- for improved regulatory efficiency. The ASCO Post. Available from: https:// indus try ascop ost. com/ issues/ octob er- 25- 2015/ delays- in- drug- appro val- are- 18. FDA (1988) Available from: https:// archi ves. feder alreg ister. gov/ issue_ deadly- highl ighti ng- the- need- for- impro ved- regul atory- effic iency/slice/ 1988/ 10/ 21/ 41492- 41527. pdf# page= 25. Accessed 13 Jan 2023 4. Potter CJ, Yuan H, Cauchon NS, Chang LL, Blaettler D, Kin DW, Millili PG, 19. FDA. Guidance for Industry Expedited Programs for Serious Conditions - Mazzola G, Ocheltree T, Tyler SM, Taber G, Watson TJ (2019) Accelerated Drugs and Biologics (2014) Available from: https:// www. fda. gov/ media/ Pharmaceutical product development, registration, commercialization, 86377/ downl oad. Accessed 22 Aug 2022 and life cycle CMC lessons, Part 1. Pharmaceutical Engineering. Available 20. FDA. Advancing Health Through Innovation: New Drug Therapy Approvals from: https:// ispe. org/ pharm aceut ical- engin eering/ ispeak/ accel erated- CDER 2021 Available from: https:// www. fda. gov/ media/ 155227/ downl pharma- produ ct- devel opment- regis trati on oad. Accessed 20 Aug 2022 5. Potter CJ, Yuan H, Cauchon NS, Chang LL, Blaettler D, Kin DW, Millili PG, 21. FDA. CBER Regenerative Medicine Advanced Therapy (RMAT ) Approvals Mazzola G, Ocheltree T, Tyler SM, Taber G, Watson TJN (2019) Accelerated (2022) Available from: https:// www. fda. gov/ vacci nes- blood- biolo gics/ pharmaceutical: product development, registration, commercialization & cellu lar- gene- thera py- produ cts/ cber- regen erati ve- medic ine- advan ced- life cycle CMC lessons, Part 2. Pharmaceutical Engineering. Available from: thera py- rmat- appro vals. Accessed 25 Aug 2022 https:// ispe. org/ pharm aceut ical- engin eering/ accel erated- pharm aceut 22. Algorri M, Acharya A, Bernstein J, Cauchon NS, Chen XH, Huynh-Ba K, ical- produ ct- devel opment- regis trati on Krantz C, Tao Li YL 6, McLamore S, Roberts SW, Schwinke D, Shah R, 6. Dye III, Groskoph ESJG, Kelley B, Millili GP, Nasr MM, Potter CJ, Thostesen Schirmer A, Strickland H, Tang K, Watson T (2022) 19 Meeting Report: ES, Vermeersch H (2015) CMC Considerations when a Drug Development Advancing Accelerated Regulatory Review with Real-Time-Oncology Review Project is Assigned Breakthrough Therapy Status Pharmaceutical Engineer- (RTOR), Project Orbis, and the Product Quality Assessment Aid AAPS Open 8 ing. Available from: https:// ispe. org/ pharm aceut ical- engin eering/ janua Available from: https:// aapso pen. sprin gerop en. com/ artic les/https:// doi. ry- febru ary- 2015/ cmc- consi derat ions- when- drug- devel opment- proje ct#: org/ 10. 1186/ s41120- 022- 00066-1 ~: text= CMC% 20Con sider ations% 20when% 20a% 20Drug% 20Dev elopm 23. FDA. Real-time review of drug applications is now a reality (2018) 18 Sept. ent% 20Pro ject% 20is% 20Ass igned% 20Bre akthr ough% 20The rapy% 20Sta Available from: https:// www. fda. gov/ drugs/ real- time- review- drug- appli tus,- Earl% 20S. & text= Assig nment% 20of% 20Bre akthr ough% 20The rapy% catio ns- now- reali ty- septe mber- 20- 2018- issue. Accessed 22 Aug 2022 20(BT,a% 20% E2% 80% 9Ccon venti onal% E2% 80% 9D% 20dev elopm ent% 24. Feng C, Virparia R, Mui ET (2021) Analysis of the real-time oncology 20pro gram review (RTOR) pilot program for approvals of new molecular entities. Ther 7. Algorri M, Cauchon NS, Abernathy MJ (2020) Transitioning chemistry, Innov Regul Sci 55(4):881–888 manufacturing, and controls content with a structured data man- 25. EMA. Conditional marketing authorization. Available from: https:// www. agement solution: streamlining regulatory submissions. J Pharm Sci ema. europa. eu/ en/ human- regul atory/ marke ting- autho risat ion/ condi 109(4):1427–1438tional- marke ting- autho risat ion. Accessed 29 Aug 2022 8. Gardner N (2021) Data integrity and pharma 4.0. Available from: https:// 26. EMA. Orphan designation: marketing authorization. Available from: https:// www.thermofisher.com/blog/connectedlab/data-integrity-and-pharma-www. ema. europa. eu/ en/ human- regul atory/ marke ting- autho risat ion/ 4-0/?ce=E.22CMD.DS109 .06571.01&cid=E.22CMD.DS109.06571.01&iq=orphan- desig nation- marke ting- autho risat ion. Accessed 29 Aug 2022 IQLAAKGACZFALKMAXR&ef_id=CjwKCAjw1ICZBhAzEiwAFfvFhHai57BU 27. EMA. Accelerated assessment. Available from: https:// www. ema. europa. eu/ POSeo3z7VRyDsgbU6Pdbm7yrVFn_C2Csbn86fzPaCwhjARoCUvsQAvD_en/ human- regul atory/ marke ting- autho risat ion/ accel erated- asses sment. BwE:G:s&s_kwcid=AL!3652!3!563674789876!p!!g!!pharma%204.0&gclid Accessed 29 Aug 2022 =CjwKCAjw1ICZBhAzEiwAFfvFhHai57BUPOSeo3z7VRyDsgbU6Pdbm7yr 28. EMA. PRIME: priority medicines. Available from: https:// www. ema. europa. VFn_C2Csbn86fzPaCwhjARoCUvsQAvD_BwE. Accessed 10 Jan 2023eu/ en/ human- regul atory/ resea rch- devel opment/ prime- prior ity- medic 9. Reinhardt IC, Oliveira J, Ring D (2023) Industry 4.0 & the future of the phar- ines. Accessed 29 Aug 2022 maceutical industry. Pharmaceutical Engineering. Available from: https:// 29. EMA. Compassionate use. Available from: https:// www. ema. europa. eu/ en/ ispe. org/ pharm aceut ical- engin eering/ march- april- 2021/ indus try- 40- human- regul atory/ resea rch- devel opment/ compa ssion ate- use. Accessed future- pharm aceut ical- indus try. Accessed 10 29 Aug 2022 10. International Society of Pharmaceutial Engineering (ISPE). Pharma 4.0 30. Vreman RA, Heikkinen I, Schuurman A, Sapede C, Garcia JL, Hedberg N, Available from: https:// ispe. org/ initi atives/ pharma- 4.0. Accessed 13 Sept Athanasiou D, Grueger J, Leufkens HGM, Goettsch WG (2019) Unmet 2022 Medical need: an introduction to definitions and stakeholder percep - 11. QbDVision. (2020) ICH, QbD, Pharma 4.0: One and the Same. Available from: tions. Value in Health 22(11):1275–1282 https:// www. qbdvi sion. com/ ich- qbd- pharma/. Accessed 22 Aug 2022 31. EMA. Annual Report (2021) Available from: https:// www. ema. europa. eu/ 12. Ahluwalia K, Abernathy MJ, Beierle J, Cauchon NS, Cronin D, Gaiki S, Len-en/ docum ents/ annual- report/ 2021- annual- report- europ ean- medic ines- nard A, Mady P, McGorry M, Sugrue-Richards K, Xue G (2021) The future agency_ en. pdf. Accessed 13 Jan 2022 of CMC regulatory submissions: streamlining activities using structured 32. EMA (2022) EMA initiatives for acceleration of development support and content and data management. J Pharm Sci 111(5):1232–1244 evaluation procedures for COVID-19 treatments and vaccines. Available 13. Helfand C (2019) If pharma looks slow to adopt AI, it’s got good reason, from: https:// www. ema. europa. eu/ en/ docum ents/ other/ ema- initi atives- expert says. FIERCE Pharma. Available from: https:// www. fierc ephar ma. accel erati on- devel opment- suppo rt- evalu ation- proce dures- covid- 19- com/ marke ting/ if- pharma- looks- slow- to- adopt- ai- there-s- good- reason- treat ments- vacci nes_ en. pdf. Accessed 13 Jan 2023 expert. Accessed 12 Jan 2023 33. Marinus R, Mofid S, Mpandzou M, Kühler TC (2022) Rolling reviews during 14. Manzano T, Canals A (2022) Measuring Pharma’s Adoption of Industry 4.0. COVID-19: the European Union experience in a global context. Clin Ther Pharmaceutical Engineering. Available from: https:// ispe. org/ pharm aceut 44(3):352–363 ical- engin eering/ janua ry- febru ary- 2022/ measu ring- pharm as- adopt ion- 34. PMDA (2021) Expedited regulatory pathways in Japan. Available from: indus try- 40https:// www. youtu be. com/ watch?v= P6z3M GDhYh4. Accessed 13 Jan 15. Hwang TJ, Darrow JJ, Kesselheim AS (2017) The FDA’s expedited pro- 2023 grams and clinical development times for novel therapeutics, 2012–2016. 35. Tanaka M, Idei M, Sakaguchi H, Kato R, Sato D, Sawanobori K, Kawarasaki JAMA 318(21):2137–2138 S, Hata T, Yoshizaki A, Nakamura M, Ikuma M (2021) Achievements and 16. Friends of Cancer Research (2023) Modernizing expedited development challenges of the Sakigake designation system in Japan. Br J Clin Pharma- programs. Friends of Cancer Research Annual Meeting 2020. Available col 87(10):4027–4035 from: https:// frien dsofc ancer resea rch. org/ wp- conte nt/ uploa ds/ Moder 36. MHLW (2020) Notification: PSEHB/PED No. 0831/6: handling of designa- nizing_ Exped ited_ Devel opment_ Progr ams- 2020_0. pdf. Accessed 12 tion of pioneer drugs 17. Beierle J, Cauchon NS, Graul TW, Hedberg Y, Holm MB, Lepore JV, 37. De Claro RA, Spillman D, Hotaki LT, Shum M, Mouawad LS, Santos GML, MacKenzie R, Mistry K, Qian X, Robinson K, Rullo G, Tang KT, Watson T Robinson K, Hunt M, Healy C, Chan A, Looi YH, Rodrigues C, Rohr UP, (2022) Toward a single global control strategy: industry study Pharmaceu- Walther C, Pazdur R (2020) Project Orbis: Global Collaborative Review tical Engineering. Available from: https:// ispe. org/ pharm aceut ical- engin Program Clin Cancer Res 26(24):6412–6416 Beierle et al. AAPS Open (2023) 9:11 Page 18 of 19 38. FDA. Project Orbis (2022) Available from: https:// www. fda. gov/ about- fda/ 55. IBM. What is a data fabric? Available from: https:// www. ibm. com/ topics/ oncol ogy- center- excel lence/ proje ct- orbis. Accessed 29 Aug 2022data- fabric. Accessed 14 Sept 2022 39. ICMRA. Pharmaceutical quality - regulatory collaboration pilots: call for 56. ArborSys. Structured content management solutions. Available from: http:// industry applications Available from: https:// icmra. info/ drupal/ strat egici www. arbor sys. com/ struc tured- conte nt- manag ement- solut ions. html. nitat ives/ pqkms/ pq_ pilots_ call_ for_ indus try_ appli catio ns. Accessed 29 Accessed 30 Aug 2022 Aug 2022 57. DitaExchange. Structured content management for financial services. Avail- 40. ICMRA (2022) A regulatory pharmaceutical quality knowledge manage- able from: https:// ditae xchan ge. com/ finan cial- servi ces/. Accessed 30 ment system (PQ KMS) to enhance the availability of quality medi- Aug 2022 cines. Available from: https:// www. icmra. info/ drupal/ strat egici nitat ives/ 58. ESKO. Customer case studies. Available from: https:// www. esko. com/ en/ pqkms/ joint_ refle ction_ paper . Accessed 16 Sept 2022brands/ case- studi es. Accessed 30 Aug 2022 41. ICMRA. International Coalition of Medicines Regulatory Authorities (2022) 59. OpenText . Read customer success stories. Available from: https:// www. Available from: https:// icmra. info/ drupal/ en. Accessed 29 Aug 2022opent ext. com/ custo mers. Accessed 30 Aug 2022 42. ICMRA. ICMRA-industry virtual workshop report on enabling manufactur- 60. Richardson M (2022) Data management matters. Aerospace Manufactur- ing capacity in the COVID-19 pandemic (2021) Available from: https:// ing 2020 23 November 2020. Available from: https:// www. aero- mag. www. icmra. info/ drupal/ sites/ defau lt/ files/ 2021- 10/ covid- 19_ manuf actur com/ data- manag ement- matte rs/. Accessed 30 ing_ capac ity_ ws_ report. pdf. Accessed 10 Jan 2023 61. Studer S Component content management use cases. Zia Consulting 2020 43. An Industry proposal: recommendations to support the rapid increase of 22 Apr 2020. Available from: https:// www. ziaco nsult ing. com/ compo manufacturing capacity for the production of COVID-19 therapeutics and nent- conte nt- manag ement/ use- cases/. Accessed 14 Aug 2022 vaccines. ICMRA workshop on enabling manufacturing capacity in the 62. Cognition (2022) Why pharmaceutical companies look to lighthouse to gen- COVID-19 pandemic 2021 28 June Available from: https:// www. ifpma. erate electronic reports for CMC-related submissions Available from: https:// org/ wp- conte nt/ uploa ds/ 2021/ 07/ Indus try_ Propo sal_ Mfg_ Capac ity_ fs. hubsp otuse rcont ent00. net/ hubfs/ 250507/ Why% 20Pha rmace utical% COVID- 19- v18Fe b2021_ revJu ne2021. pdf. Accessed 2220Com panies% 20Look% 20to% 20Lig hthou se% 20to% 20Gen erate% 20Ele 44. EMA. Welcome to IRIS. Available from: https:// iris. ema. europa. eu/. ctron ic% 20Rep orts% 20for% 20CMC- relat ed% 20Sub missi ons_ Drug% 20Sta Accessed 02 Sept 2022bility_ Cogni tion% 20Cor porat ion_ Janua ry% 202022. pdf. Accessed 14 July 45. Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, Bi Y, Liu J, 2022 Rahman A, Wearne E, Ojofeitimi I, Hotaki LT, Spillman D, Pazdur R, Beaver 63. Docuvera Efficiently create and update CMC documentation throughout JA, Singh H (2022) FDA approval summary: sotorasib for KRAS G12C- the entire pharmaceutical manufacturing process. Available from: https:// mutated metastatic NSCLC. Clin Cancer Res 28(8):1482–1486docuv era. com/ chemi cal- manuf actur ing- and- contr ols/. Accessed 30 Aug 46. Popkin ME, Goese M, Wilkinson D, Finnie S, Flanagan T, Campa C, Clinch A, 2022 2022 Teasdale A, Lennard A, Cook G, Mohan G, Osborne MD (2022) Chemistry 64. QbDVision. Discover all your knowledge can do Available from: https:// manufacturing and controls development, industry reflections on manu-www. qbdvi sion. com/ struc tured- platf orm/ facture and supply of pandemic therapies and vaccines. AAPS J. 24(6):101 65. Veeva IDMP Readiness Center. Available from: https:// www. veeva. com/ 47. EMA. Toolbox guidance on scientific elements and regulatory tools to produ cts/ vault- platf orm/ vault- rim- idmp- resou rce- hub/ support quality packages for PRIME and certain marketing authorisation 66. Lorenz Product information and lifecycle management with LORENZ applications targeting an unmet medical need (2022) Available from: drugTrack. Available from: https:// www. lorenz. cc/ Solut ions/ idmp/ https:// www. ema. europa. eu/ en/ docum ents/ scien tific- guide line/ toolb 67. GitHub IDG (2022) Automate your workflow from idea to production. Avail- ox- guida nce- scien tific- eleme nts- regul atory- tools- suppo rt- quali ty- data- able from: https:// github. com/ featu res/ issues. Accessed November 29 packa ges- prime- certa in_ en. pdf 2022 48. FDA. PDUFA reauthorization performance goals and procedures fiscal 68. Tranchard S (2017) Revised IDMP standards to improve description of year 2023 through 2027 (2022) Available from: https:// www. fda. gov/ medicinal products worldwide. ISO. Available from: https:// www. iso. org/ media/ 151712/ downl oad. Accessed 10 Aug 2022news/ ref22 34. html 49. Food and Drug Administration Federal Register. Quality Management 69. EMA. Substance, product, organisation and referential (SPOR) master data. Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Available from: https:// www. ema. europa. eu/ en/ human- regul atory/ resea Product Manufacturers; Program Announcement (2020) Available from: rch- devel opment/ data- medic ines- iso- idmp- stand ards/ subst ance- produ https:// www. feder alreg ister. gov/ docum ents/ 2020/ 10/ 16/ 2020- 22976/ ct- organ isati on- refer ential- spor- master- data quali ty- manag ement- matur ity- for- finis hed- dosage- forms- pilot- progr am- 70. Miglierini G (2022) The transition towards EMA’s new Digital Appliation for- domes tic- drug- produ ct. Accessed 10 Dec 2022 Dataset Integration (DADI) user interface. EIPG. Available from: https:// eipg. 50. FDA. Manual of Policies and Procedures MAPP 5015.13 “Quality assess-eu/ the- trans ition- towar ds- ema- new- digit al- appli cation- datas et- integ ment for products in expedited programs” (2022) Available from: https:// ration- dadi/ www. fda. gov/ media/ 162786/ downl oad. Accessed 9 Jan 2023 71. Brennan Z (2017) FDA looks to standardize PQ/CMC data and terminolo- 51. EMA. Meeting Report: Joint BWP/QWP workshop with stakeholders in gies. Regulatory Focus. Available from: https:// www. raps. org/ regul atory- relation to prior knowledge and its use in regulatory applications (2018) focus% E2% 84% A2/ news- artic les/ 2017/7/ fda- looks- to- stand ardize- pq- Available from: https:// www. ema. europa. eu/ en/ docum ents/ report/ meeti cmc- data- and- termi nolog ies ng- report- joint- biolo gics- worki ng- party/ quali ty- worki ng- party- works 72. FDA (2022) Draft pharmaceutical quality/chemistry manufacturing and hop- stake holde rs- relat ion- prior- knowl edge- its- use- regul atory- appli catio controls (PQ/CMC) data exchange. Available from: https:// www. fda. gov/ ns_ en. pdfmedia/ 157085/ downl oad. Accessed 16 52. EMA. Toolbox guidance on scientific elements and regulatory tools to 73. FDA (2022) Draft pharmaceutical quality chemistry manufacturing and support quality data packages for PRIME and certain marketing authori- controls (PQCMC) data exchange. SUPPORTING & RELATED MATE- sation applications targeting an unmet medical need (2022) 22 April RIAL. Available from: https:// www. regul ations. gov/ docum ent/ FDA- 2022- 2022. Available from: https:// www. ema. europa. eu/ en/ docum ents/ scien N- 0297- 0002. Accessed 17 Sept 2022 tific- guide line/ toolb ox- guida nce- scien tific- eleme nts- regul atory- tools- 74. HL7 (2022) Introducing HL7 FHIR. Available from: https:// hl7. org/ FHIR/ suppo rt- quali ty- data- packa ges- prime- certa in_ en. pdfsumma ry. html. Accessed 30 Aug 2022 53. EMA. Meeting Report: Workshop with stakeholders on support to quality 75. HL7 (2022) Code systems. Available from: https:// hl7. org/ FHIR/ termi nolog development in early access approaches (i.e. PRIME, Breakthrough Thera-ies- syste ms. html. Accessed 30 pies) (2018) Available from: https:// www. ema. europa. eu/ en/ docum ents/ 76. Eglovitch JS (2021) FDA taking incremental approach to launching KASA report/ report- works hop- stake holde rs- suppo rt- quali ty- devel opment- reviews. Regulatory Focus. Available from: https:// www. raps. org/ news- early- access- appro aches- ie- prime_ en. pdfand- artic les/ news- artic les/ 2021/ 11/ fda- taking- incre mental- appro ach- to- 54. Macdonald JC, Isom DC, Evans DD, Page KJ (2021) Digital innovation in launc hing- kasa medicinal product regulatory submission, review, and approvals to create 77. IPQ. FDA’s KASA and related PQ/CMC initiatives on improving CMC data a dynamic regulatory ecosystem-are we ready for a revolution? Front structuring and sharing will help support ICH M4Q revision. 2022 17 Feb Med (Lausanne) 8:660808 2022. Available from: https:// ipq. org/ fdas- kasa- and- relat ed- pq- cmc- initi B eierle et al. AAPS Open (2023) 9:11 Page 19 of 19 atives- on- impro ving- cmc- data- struc turing- and- shari ng- will- help- suppo Publisher’s Note rt- ich- m4q- revis ion/ Springer Nature remains neutral with regard to jurisdictional claims in pub- 78. Kozlowski S, FDA/PQRI Conference on Advancing Product Quality 2021 lished maps and institutional affiliations. Knowledge-Aided and Structured Application (KASA) and Pharmaceutical Quality/CMC (PQ/CMC) Update:KASA for Biologics. 5th. Available from: https:// pqri. org/ wp- conte nt/ uploa ds/ 2021/ 12/3- PQRI- KASA- for- Biolo gics_ 12-3- 21_ SKozl owski- FINAL- v1. pdf 79. Roelofs B What’s in a KASA? Knowledge-aided assessment and structured application (KASA) for biological products. Well Characterized Biotechnol- ogy Products WCBP 2022. Available from: https:// www. casss. org/ docs/ defau lt- source/ wcbp/ 2022- wcbp- speak er- prese ntati ons/ speak er- prese ntati ons- roelo fs- brian- cder- fda- 2022. pdf? sfvrsn= bdc8a 079_8 80. HLA FHIR. Data exchange industry – pharmaceutical quality (dx-PQ) (2020) Available from: https:// build. fhir. org/ ig/ HL7/ uv- dx- pq/ backg round. html 81. Tarius (2017) SAC Tracker Pharmaceutical Science and Clinical Pharmacol- ogy Advisory Committee. Available from: http:// www. sac- track er. com/ pscp- 20180 920- ba 82. Yu LX, Raw A, Wu L, Capacci-Daniel C, Zhang Y, Rosencrance S (2019) FDA’s new pharmaceutical quality initiative: knowledge-aided assess- ment & structured applications. Int J Pharmaceutics: X 1:100010 83. FDA. Modernization in Action 2022 (2022) Available from: https:// www. fda. gov/ files/ about% 20fda/ publi shed/ Moder nizat ion_ in_ Action_ 2022. pdf 84. EMA. European Medicines Agency Cloud Strategy (2022) Available from: https:// www. ema. europa. eu/ en/ docum ents/ other/ europ ean- medic ines- agency- cloud- strat egy- accel erati ng- innov ation- digit alisa tion- better- public- anima l_. pdf 85. EMA. Q&As on IRIS registration, login and RPI requests. Available from: https:// iris. ema. europa. eu/ forums/ whats- new/ b9e93 2c2- 3ad7- ea11- bf21- 0003 ff5fd6 3e. Accessed 02 Sept 2022 86. Nogueira F (2022) Welcome to Accumulus Synergy. Available from: https:// www. accum ulus. org/. Accessed 9 87. ICH. ICH Topic Q 1 A (R2) stability testing of new drug substances and products (2003) Available from: https:// www. ema. europa. eu/ en/ docum ents/ scien tific- guide line/ ich-q- 1- r2- stabi lity- testi ng- new- drug- subst ances- produ cts- step-5_ en. pdf 88. ICH (2022) History. Available from: https:// www. ich. org/ page/ histo ry. Accessed 17 89. Mezher M (2016) Going digital: EMA to ditch paper, require electronic application forms RAPS February 26, 2015. Available from: https:// www. raps. org/ regul atory- focus% E2% 84% A2/ news- artic les/ 2015/2/ going- digit al- ema- to- ditch- paper ,- requi re- elect ronic- appli cation- forms 90. EMA. Introduction to ISO identification of medicinal products, SPOR programme (2016) EMA/732656/2015. Available from: https:// www. ema. europa. eu/ en/ docum ents/ other/ intro ducti on- iso- ident ifica tion- medic inal- produ cts- spor- progr amme_ en. pdf. Accessed 17 Jan. 2023 91. FDA. Pharmaceutical quality/chemistry, manufacturing & controls (PQ/CMC). Available from: https:// www. fda. gov/ indus try/ fda- data- stand ards- advis ory- board/ pharm aceut ical- quali tyche mistry- manuf actur ing- contr ols- pqcmc. Accessed 3 Aug 2022 92. ICH. M4Q(R2) Common technical document on quality guideline (2021) Available from: https:// datab ase. ich. org/ sites/ defau lt/ files/ ICH_ M4Q- R2_ Conce ptPap er_ Endor sed_ 2021_ 1115. pdf 93. Robertson AS, Malone H, Bisordi F, Fitton H, Garner C, Holdsworth S, Honig P, Hukkelhoven M, Kowalski R, Milligan S, O’Dowd L, Roberts K, Rohrer M, Stewart J, Taisey M, Thakkar R, Van Baelen K, Wegner M (2020) Cloud-based data systems in drug regulation: an industry perspective. Nat Rev Drug Discov 19(6):365–366 94. Murali K, Kaur S, Prakash A, Medhi B (2019) Artificial intelligence in phar - macovigilance: practical utility. Indian J Pharmacol 51(6):373–376 95. Pfizer (2022) AI in drug safety: building the elusive ‘Loch Ness Monster’ of reporting tools. Available from: https:// www. pfizer. com/ news/ artic les/ ai- drug- safety- build ing- elusi ve-% E2% 80% 98loch- ness- monst er% E2% 80% 99- repor ting- tools. Accessed 16 96. Regulatory Affairs Professionals Society. RF Quarterly, Artificial intelligence (2022) December Available from: https:// www. raps. org/ news- and- artic les/ news- artic les/ 2022/ 11/ rf- quart erly- decem ber- 2022- arti ficial- intel ligen ce. Accessed 14 Jan 2023

Journal

AAPS OpenSpringer Journals

Published: May 8, 2023

Keywords: Regulatory science; Standards; Structure; Stability; Automation; Acceleration pathway; Chemistry manufacturing and controls; Structured content data management; Cloud-based systems

There are no references for this article.