A comprehensive review of 3D manufacturing and process analytical technologies in pharmaceutical quality assurance

Abstract

The assurance of pharmaceutical product quality, safety, and efficacy has historically relied on rigorous analytical standards, pharmacopoeial specifications, and the oversight of national and international regulatory authorities. While conventional regulatory frameworks and quality systems are well established for large-scale manufacturing, emerging technologies such as pharmaceutical three-dimensional printing (3DP) challenge existing paradigms, particularly in the context of personalized and small-batch drug production. Three-dimensional printing enables the fabrication of patient-specific dosage forms with tailored doses, geometries, and release profiles, offering significant advantages for paediatric, geriatric and patients experiencing polypharmacy. Despite its clinical promise, the widespread adoption of 3DP in pharmaceutical manufacturing remains constrained by fragmented regulatory guidance, limited pharmacopoeial standards, and insufficiently adapted quality assurance strategies.

This review critically examines the current regulatory landscape governing pharmaceutical 3DP, with emphasis on the approaches adopted by major regulatory bodies, including the FDA, EMA, MHRA, and ICH. The evolving role of pharmacopoeias in defining quality requirements for 3D-printed dosage forms is discussed, alongside key regulatory milestones such as the approval of Spritam® and recent investigational products. Particular attention is given to the application of Quality by Design (QbD) and Process Analytical Technology (PAT) as systematic frameworks for identifying and controlling critical quality attributes, materials, and process parameters in additive manufacturing. Finally, the review highlights persistent regulatory and technical gaps and outlines considerations necessary for the harmonized integration of 3DP into pharmaceutical practice while ensuring product quality and patient safety.

Introduction

Rigorous analytical standards and validated testing procedures were established to ensure the quality, consistency, and reliability of pharmaceutical products, which are key determinants of their safety and therapeutic efficacy. In response, the nineteenth century saw the emergence of national regulatory authorities charged with enforcing legislation to protect the public health while pharmacopoeias became the cornerstone of efforts to safeguard the quality, safety, and consistency of medicinal products [1]. These compendia provide standardised formulations and analytical methods that guide both manufacturers and healthcare practitioners. The Pharmacopoeia Europaea (European Pharmacopoeia Commission) marked the first international initiative to harmonise pharmaceutical standards, followed by the United States Pharmacopoeia (USP), first issued in 1820, and the Japanese Pharmacopoeia (JP), published in 1886. Over time, the role of pharmacopoeias has expanded, and today, numerous national and international editions continue to define the specifications for drug manufacturing, quality control, and analytical testing, ensuring that medicines consistently meet the established criteria for safety, efficacy, and performance [2].

This recognition catalysed the formation of the most prominent regulatory authorities, such as the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), World Health Organization (WHO), and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) are tasked with establishing comprehensive frameworks for the evaluation, approval, and post-market surveillance of medicinal products. Ensuring adherence to regulatory frameworks is a continuous and complex task for the pharmaceutical industry. Companies are required to comply with national and international guidelines, which are frequently revised and updated. The dynamic nature of these regulations creates significant challenges, particularly for organisations that are active in several regulatory environments. Failure to maintain compliance can lead to severe financial consequences, product withdrawal, and loss of corporate credibility [3].

In parallel with the evolution of regulatory frameworks, pharmaceutical manufacturing is undergoing a profound transformation that is reshaping the methodologies and technologies employed in drug production. The current scenario of medical treatment is centered on the paradigm “one size fits all” where most patients receive the same drugs at the same doses and frequencies as others [4]. However, the response of each patient to a specific treatment is not always identical, as it may vary according to the patient’s age, biomarker expression, and genetic characteristics [5].

Many scientific publications have focused on 3D printing (3DP) as an innovative method for personalising pharmaceutical dosage forms. The term 3D printing is defined by the International Standard Organization (ISO) as the “fabrication of objects through the deposition of a material using a print head, nozzle, or another printer technology” [6].

Additive manufacturing (AM), commonly referred to as 3DP, encompasses a broad range of technologies that differ in terms of the materials employed, deposition approaches, layer-by-layer (LbL) fabrication mechanisms, and resulting characteristics of the final products. To provide a systematic framework for these diverse processes, the American Society for Testing and Materials (ASTM) established a standardised classification that groups AM technologies into seven categories based on their fundamental technical principles: material extrusion, binder jetting, powder bed fusion, vat photopolymerization, material jetting, directed energy deposition, and sheet lamination [7].

3DP technology has shown relevance in paediatric and populations, where individualized drug delivery systems are needed to meet specific biopharmaceutical requirements, such as precise control over dosage, improved swallowability, and customizable release profiles [8].

Beyond paediatrics, 3DP has emerged as a promising strategy for producing personalized pharmaceutical dosage forms tailored to the needs of older patients [9]. Khaled et al. demonstrated the feasibility of this approach by fabricating a 3D-printed polypill that incorporated three active pharmaceutical ingredients (API) captopril, nifedipine and glipizide. Such multicomponent tablets illustrate how additive manufacturing can effectively reduce polypharmacy-related burdens in the geriatric population by consolidating multiple medications into a single, customizable dosage unit. 3DP also enables the creation of non-conventional tablet geometries designed to improve patient acceptability and tablet usability [10].

3DP facilitates the broader concept of personalized medicine by enabling flexibility in both design and dosage, increasing the flexibility in the design and fabrication of complex drug structures, and allowing precise adjustment of dosages and combinations, as well as rapid prototyping and production of devices [11].

However, several technical and regulatory challenges must be overcome to achieve widespread integration in the drug manufacturing industry, including regulatory standards, accumulating evidence to support safety and efficacy, and creating dosage forms and 3D printers that are suitable for use in the pharmaceutical industry and by other stakeholders [12].

Although agencies such as the FDA and United Kingdom’s regulatory authority (MHRA) have made progress, their guidance is often fragmented and not fully tailored to the unique challenges of personalized, on-demand manufacturing. The integration of PAT and QbD is essential for ensuring product quality and safety; however, current frameworks are not fully adapted to the dynamic and small-batch nature of 3DP [13].

The FDA approval of Spritam® 3D printed tablets in 2015 was a breakthrough in the pharmaceutical industry for the treatment of epilepsy, setting the benchmark for the first regulatory-approved pharmaceutical product 3DP technique as a novel and promising tool for the development of pharmaceutical products [14]. In February 2021, the Chinese pharmaceutical and 3DP technology company Triastek received Investigational New Drug (IND) approval from the FDA for its first and second 3D printed tablets, T19, for treating rheumatoid arthritis. They employed Melt Extrusion Deposition (MED) 3DP technology with integrated real-time Process Analytical Technology (PAT) to continually monitor the 3DP process, ensuring product quality and facilitating regulatory monitoring [15]. Quality assurance of 3D-printed dosage forms is a concerning area, and the FDA and pharmacopoeias need to develop and disseminate quality standards that are better suited to ensure the effectiveness of 3D-printed formulations [12].

In this context, Quality by Design (QbD) has emerged as an alternative approach to quality assurance in the field of pharmaceutical 3DP. QbD has been defined in the ICH Q8 guideline (EMA guideline) as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [16]. QbD provides a systematic framework for identifying and controlling Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), and Critical Process Parameters (CPPs) to ensure consistent drug quality. By incorporating risk assessment tools such as Design of Experiments (DoE) and Failure Mode and Effects Analysis (FMEA), QbD helps in predicting process variability, improving formulation stability, and facilitating the large-scale adoption of this innovative manufacturing technology [17].

Together with QbD the Process Analytical Technology (PAT) represents a fundamental component of the FDA’s initiative, introduced in August 2002. This initiative aims to enhance and modernise pharmaceutical manufacturing processes through the integration of advanced quality management and risk assessment strategies [18]. The integration of PAT tools during and after the 3DP process has been identified as a system for designing, analysing, and controlling manufacturing through timely measurements to monitor the critical quality and performance attributes of solid pharmaceutical forms (e.g. drug content) to ensure final product quality, which can be installed in-line, on-line, at-line, or off-line, supplying both qualitative and quantitative information [19].
Based on the literature considered in this review, several recurring and interrelated gaps can be identified, particularly the absence of harmonized regulatory guidance for pharmaceutical 3D printing (3DP) and the limited, non-systematic integration of Quality by Design (QbD) and Process Analytical Technology (PAT) into 3DP workflows.

Across multiple regulatory and technological analyses, it has been consistently reported that although the FDA and other agencies have issued general guidance for additive manufacturing (AM), these documents are predominantly device-focused and do not establish clear, harmonized regulatory pathways or pharmacopoeial standards for 3D-printed oral dosage forms. Current guidance (for example, FDA AM for devices) is device-oriented and explicitly states that a single standard set of rules for all 3DP methods is impossible, leaving drug products without tailored requirements for design, process validation, and Quality Control. Regulatory discourse thus remains fragmented across jurisdictions and is largely oriented toward medical devices, with no globally harmonized framework tailored to point-of-care or hospital-pharmacy manufacture of 3DP medicines [20].

In parallel, while QbD and PAT are mature concepts in conventional large-scale manufacturing, their application to on-demand-, small-batch- 3DP of medicine remain sporadic and primarily confined to proof-of-concept demonstrations. implementation of non-destructive analysis. For example NIR, and Raman) are often presented as isolated QC solutions. Consequently robust, implementable quality architectures (including real-time release testing schemes, PAT positioning, and digital data workflows) remain insufficiently specified for routine clinical or point-of-care 3DP use [21,22].

The primary objective of this review is to critically assess the existing regulatory landscape and global harmonization among major regulatory agencies (e.g. FDA, EMA, MHRA, and ICH) and explore how pharmaceutical dosage forms can be produced using 3DP technology in compliance with current regulatory expectations. Attention will be given to the potential role of pharmacopoeias’ in fostering innovation while maintaining product quality and ensuring patient safety, starting from QbD as an alternative approach to QC 3D printed dosage forms, involving the identification of critical quality attributes (CQAs) during manufacture.

This review focuses on how the implementation of PAT and QbD tools can enhance process understanding and control. The objective of this study is to justify how QbD tools enable the development of a design space and the identification of sources of process variability throughout pharmaceutical manufacturing. Several studies have applied QbD principles and PAT frameworks in pharmaceutical production, grounded in the recognition that an effective control strategy arises from a thorough understanding of the product and process, supported by systematic risk management [23].

A comprehensive examination of the current regulatory landscape governing 3D printing (3DP) in the pharmaceutical sector is also included, serving as a foundational framework for the ensuing discussion. Specifically, this review aims to do the following:

• provide an in-depth analysis of the regulatory framework currently applicable to pharmaceutical 3D printing, with reference to the approaches adopted by key authorities, such as the FDA, EMA, MHRA, and ICH;
• discuss the evolving role of pharmacopoeias in defining quality standards, safety requirements, and testing methodologies for 3D-printed pharmaceutical dosage forms.
• analyse how Quality by Design (QbD) principles can be applied to pharmaceutical 3D printing processes, with emphasis on the systematic identification and control of critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs);
• review the use of Process Analytical Technology (PAT) tools in additive manufacturing to enhance process understanding, enable real-time monitoring, and support regulatory compliance;
• highlight major regulatory and technical limitations reported in the literature, including the absence of harmonized guidance for 3D-printed medicinal products and the limited integration of QbD and PAT-driven strategies in personalized pharmaceutical manufacturing;
• This review outlines the regulatory and pharmacopoeia considerations that may support the development, quality assurance, and industrial implementation of pharmaceutical dosage forms manufactured using 3D printing technologies.

Regulatory agencies abbreviations:

• United States Pharmacopoeia (USP)
• Japanese Pharmacopoeia (JP)
• U.S. Food and Drug Administration (US FDA)
• European Medicines Agency (EMA)
• World Health Organization (WHO)
• International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH)
• International Standard Organization (ISO)
• American Society for Testing and Materials (ASTM)
• United Kingdom’s regulatory authority (MHRA)
• European Pharmacopoeia (EP)
• United States Pharmacopoeia–National Formulary (USP-NF 2024)
• Indian Pharmacopoeia Commission (IPC)

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Mariangela Totaro, Valentino Laquintana, Nunzio Denora, Dimitrios A. Lamprou, A comprehensive review of 3D manufacturing and process analytical technologies in pharmaceutical quality assurance, Journal of Drug Delivery Science and Technology, Volume 124, 2026, 108640, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108640.

Read also our introduction article on 3D Printing here: