The European Commission has adopted a strategic approach to pharmaceuticals in the environment covering all phases of their lifecycle, from design and production through to use and disposal. By advancing a roadmap of technological innovations towards both less impactful production methods and one-step disposal (where drugs are fully metabolised in the body and break down immediately and harmlessly in the environment) we can boost, and intentionally design-in, reduced environmental impact of pharmaceutical products.
The scope of ETERNAL’s R&D initiative has been designed in a co-creative process by the research/technological development teams and the pharmaceutical industry hosts of the project’s case studies. Defining specifications, industry requirements, business/environmental impact key performance indicators (KPIs) and regulatory compliance requirements for each of the case studies informs both the R&D (Technology Readiness Level 3-4) and further scale up aspects (TRL 5-6) of the ETERNAL green chemistry, mechanochemistry and digitalization innovations.
Solvents are commonly used as the reaction medium in which chemical or biochemical reactions take place to make active pharmaceutical ingredients (APIs). They are also used to purify drug substances, separating desired products from unwanted ones, and in downstream processes to formulate drug products suitable for administering to patients. It has been estimated that up to 80% of the waste arising from API manufacture is solvent related, so addressing their selection, use, recovery, and disposal can contribute dramatically to alleviating this problem. However as solvents have a great influence on the quality of the final products, it can be difficult to find suitable replacements. By applying the twelve principles of Green Chemistry using expert tools offering guidance and support, it is possible to devise green chemistry processes, opening the way, for example, to using recognized environmentally friendly solvents
Rather than using a conventional solvent-medium based approach to synthesis, a mechanochemical process involves bringing finely distributed or ground chemical substances together without the need to use solvents to distribute them. This means that no solvent-associated waste is generated, and in addition, the whole process can take place tens of times faster than a conventional reaction. Holt Melt Extrusion (HME) has emerged in recent years as a pioneering manufacturing technology for the pharmaceutical industry, and its use is growing due to its cost-effective, continuous, solvent-free nature as a unit operation.
Most natural bioactive ingredient producers also result in an (often large) number of undesired toxic side products as well as the target active. These need to be removed in subsequent purification using organic solvents and multistep chromatography. By cleaning the metabolic profile at the point of production there is the potential to reduce the volume of purification solvents and to intensify the fermentation stage, saving energy.
Pharmaceutical research projects are often outsourced to contract development and manufacturing organizations (CDMOs). Transfer processes to transfer the primary data produced by the CDMO in such projects are not standardized, requiring significant human resource for processing and reporting, too much error-prone manual data transfer activity, and too little time for analyzing and understanding the results. Primary data can get lost, and staff turnover can lead to erosion of corporate memory, resulting in repeated work and missed opportunities.
Digitizing this process to transfer data in real time and ensure that it is F.A.I.R. (Findable, Accessible, Interoperable, Reusable) can minimize the need to repeat experiments. Greater control over data should result in more sustainable, faster development of scalable production methods. Data from every experiment can contribute to the fundamental process understanding, supporting the formation of digital twins and predictive modelling. To develop a well-defined digital work flow for data transfer we will build guidelines for effective and generalizable digital data transfer. Implementation of the digital workflow will be via a software toolkit enabling application across the pharmaceutical development industry.
Process Analytical Technology (PAT) provides the means to to design, analyze, and control pharmaceutical manufacturing processes by measuring key variables of the production process (referred to as Critical Process Parameters or CPPs) which affect Critical Quality Attributes (CQAs) of the product. With sufficient understanding of the links between the two, advanced real-time monitoring and control systems can be used to keep the CPPs within defined limits and assure the quality of the product.
Continuous processing offers a range of potential advantages over traditional batchwise manufacture of pharmaceuticals: better yield, safety, and quality, and access to new chemistries that are not feasible in batch-based operations. Continuous manufacturing cannot however be supported by a traditional Quality by Testing (QbT) approach, which involves pausing for offline testing of samples after each manufacturing stage. By contrast, Quality by Design (QbD) is based on the principle that product quality should be designed into the process, and is thus philosophically well matched to continuous process control.
QbD is an approach welcomed by the European Medicines Agency. It aims to ensure the quality of medicines by employing statistical, analytical and risk-management methodology in the design, development and manufacturing of medicines. PAT is a key enabler for QbD as it provides a systematic structure for measuring product quality in real-time, facilitating process understanding and ultimately controlling the process to ensure product quality.
A Digital Twin is a virtual model of a process, product, or service. A Digital Twin offers the ability to optimize the process at low risk and cost, and avoid problems before they occur in reality, by monitoring virtual systems and process performance, and conducting analysis of data arising from the virtual operation. Digital Twins can also allow new developments and process innovations to be modelled using digital simulations, to foster new opportunities.
In ETERNAL we are employing a multivariate data driven approach and some hybrid concepts which are better suited for developing reliable models for complex biochemical systems than traditional first principals and simple empirical data based modelling. We are also using agent-based digital twinning to handle system complexity, splitting the entire system model into autonomous agents or “holons”. A Holonic Manufacturing System (HMS) is formed by holons and groups of holons that cooperate proactively to reach a common goal. In ETERNAL, we will define a new Holonic Reference Architecture in the field of Intelligent Manufacturing Systems (IMS) specially tailored for continuous manufacturing processes.
Compliance-by-Design is a thread running through ETERNAL’s innovation across all the enabling technologies being developed. Latest developments from scientific review, regulation, and marketing authorization procedures in the respective fields will be used to inform a ‘compliant-by-design’ strategy in relation to the developments as part of the ETERNAL cocreation process.
As part of our overall assessment of the opportunities and barriers for digitalization of the European pharmaceutical industry we will asses the regulatory implications and any hurdles currently posing a barrier to digitalization, making recommendations towards a more enabling regulatory framework, without compromising access to safe and effective medicinal products.
It is a key part of the Regulator’s role to ensure that risk to the patient is minimized, whatever method is is use to manufacture a medicine. Replacing, where possible, hazardous solvents with more environmentally acceptable options can lead to intrinsically safer medicines by even further reducing any manufacturing residues that may be present.
We will perform targeted studies assessing the toxicity of pharmaceuticals and their by-products to ecosystems, use mathematical models to predict their transport into and around the environment, collate monitoring data, and produce a roadmap for integrating new scientific knowledge into regulatory risk assessment.
Bringing the latest scientific knowledge into regulatory risk assessment will enable us to rank current in-use pharmaceuticals in terms of those that pose the greatest environmental risk, and to assess how the modifications made within the project case studies reduce risk. This will allow us to target mitigations, modifications and management strategies, ultimately towards a greener, more sustainable environment.
We are reaching out to those involved in industrial, regulatory, healthcare and consumer aspects of the pharmaceuticals lifecycle through a Change Labs approach, complementing the project’s technological innovations. By effectively engaging these groups, we can raise awareness of current issues in the pharmaceutical lifecycle, and inform them of the role that they can play in the Greener Pharmaceuticals movement for positive impact.
We will be organizing technical demonstrations, webinars and events to provoke interest from industrial decision makers. Policy making working groups will be provided with with support to understand scientific evidence to promote change to a ‘pull’ approach to regulatory frameworks, whereby industry will be encouraged to ‘re-validate’ their processes towards greener routes. Working with existing specialist NGOs and building on current initiatives, we will co-design a Greener Pharmaceuticals Pledge/Safe Disposal Ambassadors programme and elements of a future social media campaign with a pilot group of healthcare practitioners to promote education of patients on the importance of safe disposal of unused medication, prescribing of green pharmaceuticals and responsible prescribing of drugs.
This is inherent in our overall goals and purpose. Ongoing access to safe, high quality and effective pharmaceutical treatments is vital for fair and fulfilled living. This cannot however be at the expense of undue impacts upon the environment. Indeed human health and the health of the environment go hand in hand. Ultimately the enhanced processes and workflows enabled by ETERNAL’s innovations will accelerate and secure cost-competitive manufacture of high quality medicines, whilst the new scientific knowledge generated about the environmental risks and fates of medicines will help to ensure that the benefits are realised in ways consistent with the needs of the environment.
Careful consideration, management and mitigation of scale-up risks is an integral part of the ETERNAL work plan. Additionally, one of the benefits of the digitalization approaches being employed is that they allow problems to be anticipated in the virtual world so that they can be prevented before they have a chance to occur for real. Looking at scale-up more broadly, our roadmap for post-project deployment will be built upon thorough risk assessments, compliance and environmental impact reports.
Like any R&D project that of course remains to be seen, however we believe the selected technological approaches and underlying science are fundamentally sound and applicable to the challenges targeted. We also have confidence in the ETERNAL co-creative process defining the specifications, industry requirements, business and environmental impact KPIs and regulatory compliance requirements by which our case studies will be steered.
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