Life cycle assessment of pharmaceutical tablet manufacturing: A comparative analysis and systems model integration framework

Abstract

Pharmaceutical drug products in the form of tablets are produced via a series of manufacturing steps, transforming powder blends to compacted granules with carefully selected properties such as tensile strength and dissolution time. Typical oral solid dosage form (OSD) manufacturing processes include direct compression (DC), roller compaction (RC), high shear granulation (HSG) and continuous direct compression (CDC). Design of each process step is required to achieve end-product quality for the specific material properties and available equipment, although design decisions are typically made without a quantitative understanding of the impact on product environmental footprint. Using a ‘cradle to gate’ life cycle assessment (LCA) methodology, a quantitative sustainability comparison has been made between standard OSD manufacturing platforms across different production scales. The results demonstrate that for small batch sizes, DC produces tablets with the lowest carbon footprint, however at larger batch sizes, CDC is the most carbon efficient manufacturing platform. Due to the high carbon footprint of the active pharmaceutical ingredient (API), formulation process yields had the greatest impact on overall carbon footprint, although emissions from equipment energy, cleaning and facility overheads were also analysed. Data from these LCA models has been combined with systems models of the CDC manufacturing processes. These combined models are used to demonstrate the optimisation of processes to meet robust product quality attribute targets whilst identify opportunities to minimise the drug product carbon footprint.

Introduction

Due to the complex nature of pharmaceuticals, their production presents a significant environmental burden (Debaveye et al., 2016). Active pharmaceutical ingredient (API) synthesis often demands complex chemistry and multiple-step reaction pathways which can be highly resource intensive, leading to a global warming potential (GWP) 25 times larger than that of a basic chemical (Chen et al., 2024; Wernet et al., 2010). Specialised excipients are often then required to formulate the drug product resulting in the pharmaceutical industry’s large carbon footprint, which is shown to have greater emissions than the automotive industry (Belkhir and Elmeligi, 2019; van der Merwe et al., 2020). The pharmaceutical industry is facing increasing pressure to improve sustainability, and in particular, reducing carbon emissions is becoming a growing challenge. The manufacture of pharmaceuticals contributed close to a third of the overall carbon footprint for Britain’s National Health Service (NHS) in 2019 (Tennison et al., 2021). With health systems beginning to implement targets for greenhouse gas emissions, pharmaceutical companies are focusing on reducing their carbon footprints (Booth et al., 2023).

Oral solid dosage forms (OSD), most commonly tablets and capsules, are typically the most popular pharmaceutical dosage form, owing to their convenient administration, safety and stability (Shaikh et al., 2018). This paper concerns selection and optimisation of OSD manufacturing platforms to reduce environmental impacts, primarily focusing on tablet manufacturing. Broadly speaking, the manufacturing process for tablets can be split into two key routes; direct compression (DC), and granulation followed by compression (Leane et al., 2015). DC consists of blending active pharmaceutical ingredient (API) with excipients such as fillers, binders and lubricants, and compacting the powder into a tablet. DC is predominantly carried out as a batch process, although continuous direct compression (CDC) is an emerging technology, with recent FDA approvals including Prezista® (Lyytikäinen et al., 2024). Granulation can generally be split into wet granulation and dry granulation techniques and although several granulation methods exist, this paper focuses on high shear granulation (HSG) and roller compaction (RC). HSG involves a dry mixing step of powders, followed by addition of a liquid binder and a wet massing stage where particles aggregate, forming granules (Liu et al., 2021). A subsequent drying step is required after the granulation process, and a milling step is commonly used to reduce oversized granules. RC involves feeding a powder blend through counter-rotating rolls. The rolls exert mechanical force on the powder, producing a compacted ribbon which is then milled to form granules (Freeman et al., 2016).

Life cycle assessment (LCA) evaluates the environmental impacts a product has over its lifetime, producing a quantitative measure which can be used to identify sources of environmental impacts and drive sustainable development. LCA has been used to quantify environmental impacts in the pharmaceutical industry for both API synthesis and drug product manufacture, such as in (Parvatker et al., 2019), (Siegert et al., 2020) and (Wang et al., 2021). One recent publication by (Hadinoto et al., 2022) assesses environmental impacts of ibuprofen tablets produced by wet granulation and DC, including the influence of production scale. Sustainability comparisons have also been made between different granulation methods by (Karunanayake et al., 2024), focusing on energy consumption, material use and time. Additionally, comparisons between batch and continuous processing have been made for drug substance manufacturing and wet granulation (De Soete et al., 2013; Lee et al., 2016). There is however a lack of holistic LCA comparisons between process technologies used in OSD manufacturing, and at present there are no LCAs covering CDC available in literature.

Although approaches to LCA have been standardised within ISO 14040, the methodology of current LCAs in literature varies with differences in scope and impact assessment categories. One consistent finding in most work reviewed is the challenges encountered with data availability (Chen et al., 2024), (Cespi et al., 2015). There are several methods in literature for estimating missing life cycle inventory (LCI) data, and a hierarchy of these methods has been presented by (Parvatker and Eckelman, 2019). While there are a few examples of excipient material LCAs available in literature, such as microcrystalline cellulose, (Katakojwala and Mohan, 2020), LCI data is particularly difficult to find for pharmaceutical grade excipients. As such, it is often necessary to use a proxy value or rely on process calculations to estimate these values (Huber et al., 2022).

Pharmaceutical process design and optimisation is increasingly guided by digital activities such as systems modelling. System models, sometimes referred to as ‘digital twins’, are created by the connection of process models for multiple unit operations, connected as in the physical system. This enables simulation of the relationship between material properties and process settings across different process stages, and end-product qualities. A number of system models of the CDC process have been described in the recent literature, for example by (García-Muñoz et al., 2018), (Tian et al., 2021), and (Moreno-Benito et al., 2022). Inclusion of LCA models in system models is a natural extension, allowing a more holistic assessment that includes the impact of material and process choices on both the product quality attributes and the sustainability of the overall process, facilitating the identification and selection of more sustainable manufacturing processes and settings.

In this study, a ‘cradle-to-gate’ LCA methodology was used to perform a quantitative sustainability comparison between standard OSD manufacturing platforms: RC, DC, HSG and CDC. Since carbon footprint data was more readily available for materials used in the formulation, global warming potential (GWP) was selected as the impact category for the study. An LCA was performed for each manufacturing platform across different manufacturing scales. The LCA examined impacts relating to materials, energy consumption from equipment and facility overheads, as well as cleaning and waste impacts. Additionally, the LCA models were coupled with a system model for a CDC process to assess sustainability impacts relating to process parameters in a framework that would allow for process design and optimisation to consider carbon cost alongside product quality and productivity metrics. This paper is structured as follows: Section 2 presents an overview of the key steps and material flows in different OSD manufacturing processes, followed by a description of modelling choices and process settings used here; 3 Life cycle assessment methodology, 4 Systems modelling methodology present the LCA and system modelling methodologies; Section 5 presents results for each (stand-alone LCA calculations and system model with embedded LCA calculations); and Section 6 presents the conclusions.

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Table 1. Tablet core formulation for a generic API to be used in all platform comparisons.

Following excipients are mentioned in the study besides others: Partek M200 and Pearlitol 200SD

Flora Bouchier, Astrid Boje, Gavin Reynolds, Life cycle assessment of pharmaceutical tablet manufacturing: A comparative analysis and systems model integration framework, International Journal of Pharmaceutics: X, 2025, 100395, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100395.

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