Scoping Review to Identify Data Needs and Environmental Hotspots for Future LCA Studies: Insights into Pharmaceutical Excipients and Processes

Abstract

In recent years, the environmental assessment and optimization of pharmaceutical dosage forms have received increasing attention. Consequently, interest in Life Cycle Assessments (LCA) has grown, and LCA is rapidly becoming the standard method of environmental evaluations across many industries, including the pharmaceutical sector. LCA is, however, a high entry barrier method requiring expertise, software- and database access, and process specific experimentally obtained performance data (e.g. electricity consumption).

In the context of pharmaceuticals, significant challenges arise due to the limited availability of input data. Because of these limitations, we wanted to investigate the feasibility of using a scoping review as an alternative to LCA for evaluating the environmental implications of pharmaceuticals. In this literature review, a total of 8788 articles were screened, of which 117 were relevant. The search was anchored in a formulation previously developed.

In this formulation, 3.0 mm minitablets were manufactured by direct compression from a spray-dried amorphous solid dispersion of indomethacin in polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) with the additional use of milled lactose monohydrate (LACT), microcrystalline cellulose (MCC) and magnesium stearate (MgSt) as tablet excipients. Through the systematic literature review, relevant environmental information was found for most of the processes and excipients investigated. Research currently undertaken at the intersection of environmental review and pharmaceutical manufacturing shows an upward trend.

Most notably, recent research indicates that excipients generally regarded as safe (GRAS) may not necessarily be without environmental concern. Furthermore, excipients may be manufactured through multiple different routes which muddles the environmental comparison of different options. Still, this literature review identified a marked absence of sustainability-themed research specific to pharmaceutical manufacturing. With the issues uncovered, more research is sorely needed to provide guidance in formulation choices.

Introduction

Throughout the preceding decade, the environmental impacts of pharmaceutical manufacture and the use of pharmaceuticals have become increasingly evident (Belkhir and Elmeligi 2018, Milanesi et al. 2020). Pharmaceuticals and pharmaceutical treatment constitute an integral part of services offered by health care providers, and their contributions to the greenhouse emissions stemming from health care activities are estimated at 8 % worldwide (Lenzen et al. 2020). Local contributions may vary significantly, as illustrated by the 25 % contribution reached in a similar study based in the United Kingdom (NHS 2020). These findings corroborate earlier observations emphasizing the emission intensiveness of the pharmaceutical industry (Belkhir and Elmeligi 2019). Recent research approaching the topic by means of life cycle -methodology accentuates the environmental harm caused by the high energy, raw material and solvent consumptions associated with pharmaceutical manufacture (Chen et al. 2024).

Drug-related environmental harm is, however, not limited to the emission of greenhouse gases. Despite correct usage, human excretion of active pharmaceutical ingredient (API) residues into municipal wastewater is a major route whereby pharmaceuticals reach the environment (Kümmerer 2010). A wide range of API residues have been found to accumulate in surface waters and marine sediments, which causes concern for harmful effects to non-target organisms (Kötkö et al. 2019; Rojewska et al. 2025; Sanderson et al. 2024; Wilkinson et al. 2022). Even more so, the accretion of a multitude of APIs in the presence of other pollutants, possibly as well under irregular conditions such as oxygen depletion or elevated temperature, causes synergistic exposures that may concentrate unevenly across wildlife species (Kidd et al. 2024). Noting the sheer range of APIs in clinical use, it ought to give pause that the potential negative effects of these to ecosystems are largely unknown (Bean et al. 2024). Nevertheless, the severity of the risks is clearly demonstrated by the well confirmed case of NSAID-induced harm to avian scavengers in the early 2000s (Oaks et al. 2004; Schulz et al. 2004).

Consequently, the environmental evaluation of pharmaceuticals is receiving increased attention (Becker et al. 2022). Thus far, these efforts have primarily centered around waste-reduction strategies in relation to the manufacture of APIs, e.g. by employing process mass intensity (PMI) (Jimenez-Gonzalez et al. 2011). The PMI approach aims to optimize resource consumption by reducing the total mass of raw materials required to manufacture a given mass of API. Recently, improvements to the PMI formula target the impact of the auxiliary operations necessary to maintain the condition of the manufacturing equipment. Termed manufacturing mass intensity (MMI), MMI includes factors describing the total mass of e.g. cleaning agents, organic solvents and rinsing water consumed immediately before or after the manufacture of a given mass of API (Benison and Payne 2022). While the inclusion of these substances is commendable and broadens the domain of sustainability optimization, PMI and MMI both suffer from the fundamental flaw that all mass reduction is assigned equal environmental value (Sheldon 2017).

As has been uncovered in life cycle assessments (LCAs), the environmental impact exerted on e.g. marine ecotoxicity or terrestrial ecotoxicity per kilo of raw material consumed varies with the material in question (Hadinoto et al. 2022a; Siegert et al. 2020; Tao et al. 2023). In addition to the detailed analysis of its constituents including the API(s), excipients and other necessary substances not present in the final product, further advantages of the LCA model is the generation of environmental metrics across all life stages of the pharmaceutical: raw material acquisition, manufacture, transport, use and disposal of the product; thus, also tracking energy expenditure and emissions (Jimenez-Gonzalez and Overcash 2014).

The LCA methodology is an iterative process consisting of four stages: 1. Goal and scope definition, 2. The collection/creation of life cycle inventory (LCI), 3. Assessment of the life cycle impact (LCIA), and 4. Interpretation of the results (ILCD Handbook 2010). Resources and guidelines for conducting LCAs exist in literature (ILCD Handbook 2010, ISO 14040/14044 2006; Jimenez-Gonzalez and Overcash 2014; Siegert et al. 2019). The most laborious process is the inventory (LCI) phase, which includes the systematic gathering and documentation of data on the inputs and outputs associated with each stage of a product’s life cycle, including raw material extraction, manufacturing, distribution, use, and disposal, to assess its environmental impact. While the data potential within the LCA -framework is substantial, when applied, the scope of study is often limited to a section of the supply chain, e.g. “cradle-to-gate” (raw material acquisition to factory departure gate), distribution, n or end-of-life (waste management) scenarios. This limitation in scope is problematic because it complicates the overall sustainability profile of pharmaceuticals. Moreover, optimizing the supply chain and manufacturing processes based on incomplete data may inadvertently shift the environmental burden by disregarding new sustainability issues that have formed in areas not investigated.

Of the LCA literature currently available, most studies are comparative in nature which limits their application in other contexts because of the lack of absolute metrics (Chen et al. 2024). LCAs are complex, requiring expertise and data that can be difficult to acquire. So far, the LCA of pharmaceuticals face significant challenges with regard to data availability (Satta et al. 2024). It has proven difficult to obtain detailed inventory data from the pharmaceutical industry because of proprietary reasons, which limits both the scope and quality of LCA. Even though the methodological approach would be well-documented and rigorous, the reliability of results relies on the quality of the input data. Furthermore, it should be noted that the issues of environmental manufacture of pharmaceutical dosage form do not exist in a vacuum. Sustainable manufacture must be considered within the purview of critical process concerns such as e.g. the poor powder flowability or aqueous solubility of an API. Thus, a major challenge of the pharmaceutical industry is the translation of sustainability research into actionable knowledge.

In our recent study focusing on developing a sustainable dosage form, we adopted an approach in where the number of processes and formulation excipients were kept at minimum (Autzen Virtanen et al. 2024). A simple, two-filler formulation was successfully developed for the direct compression (DC) of minitablets, with the formulation challenges of poor flow and solubility of the API. The present study employs a scoping review to examine the excipients and common manufacturing processes associated with the previously developed tablet formulation (model tablet). The objective is to evaluate the environmental impact of these components throughout the life cycle of the model tablet. This approach aims to provide insights regarding environmental implications, in the absence of computational modelling (LCA). Through the identification of environmental hotspots, the goal is to inform pharmaceutical product development and enable the targeting of sustainability optimization efforts to areas in which the greatest impact can be achieved.

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Materials and Methods

This study is a continuation of previous work detailing the direct compression manufacture of 3.0 mm minitablets from a spray-dried amorphous solid dispersion of indomethacin in polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) with the additional use of milled lactose monohydrate (LACT), microcrystalline cellulose (MCC) and magnesium stearate (MgSt) as tablet excipients (Autzen Virtanen et al. 2024). With the objective of sustainable manufacturing, the number of processes and excipients were purposely kept to a minimum in the development of this formulation. Furthermore, given the high prevalence of poorly water-soluble active pharmaceutical ingredients (APIs) in formulation development, indomethacin, classified as a poorly soluble yet highly permeable Biopharmaceutical Classification System (BCS) Class II compound, was selected as the model API for this study.

Based on the excipients and processes (Table 1) relating to the previously developed tablet formulation, a thorough search for applicable literature describing the environmental effects of manufacture was conducted using the following databases: Elsevier ScienceDirect, Web of Science, and Scopus. To reflect the substantial development which has occurred within the fields of sustainability and environmental methodology in recent years, the review period was limited to the years 2015 to 2025. Search terms indexed in the MeSH database were prioritized, however, due to the emerging nature of the topic, supplementary keywords were added to ensure comprehensive coverage. The search term “sustainability” was interpreted as environmental sustainability and somewhat economical sustainability, e.g. in relation to the cost of manufacturing. Social sustainability was excluded. The search term “environmental impact” was interpreted broadly to include any impact on the environment. The results were identified and screened using the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guideline (Page et al. 2021). PRISMA is a comprehensive workflow and checklist tool for the structured synthesis and reporting of insights used in systematic reviews and meta-analyses. Using this methodology, the assumptions and choices underpinning the selection process are disclosed, which enhances the clarity and traceability of the results. The process as it was applied in this study is illustrated in Fig. 1 below.

Anja Autzen Virtanen, Satu Lakio, Atif Madi, Mia Sivén,
Scoping Review to Identify Data Needs and Environmental Hotspots for Future LCA Studies: Insights into Pharmaceutical Excipients and Processes,
European Journal of Pharmaceutical Sciences, 2026, 107453, ISSN 0928-0987,
https://doi.org/10.1016/j.ejps.2026.107453.