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Advanced intelligence and close-loop control for Crystallisation of API’s (Active Pharmaceutical Ingredients)

Periodic Reporting for period 2 - SmartCrys (Advanced intelligence and close-loop control for Crystallisation of API’s (Active Pharmaceutical Ingredients))

Reporting period: 2020-03-01 to 2021-02-28

PROBLEM: 1 of the biggest challenges for the Pharma industry is to ensure timely and reliable access to safe, innovative, and cost-effective medicines. High-quality APIs require both consistent physical and chemical properties. The crystallisation step is critical in determining both physical properties & the final purity of the API. These properties can have a significant effect on the drug product behaviour and quality, such as blend homogeneity, drug absorption rate, dissolution and process & product robustness. Also, chemistry-specific variation including polymorphism, purity and moisture content can have a critical effect on drug product quality, bioavailability, safety and shelf life.
We have identified the following pain points among our API mfg client base.
Pain Point #1. Poor control and efficiency of the crystallization process.
Soln: SmartCrys consists of an integrated soln of PAT analysers, Mfg Intelligence, Process Automation and Data Storage and Analytics which will lead to a controlled, efficient, mfg process with the ability to quickly self-adjust process parameters, to compensate for variability in process performance thus resulting in consistent product of the appropriate quality.
Pain Point #2. Regulators are taking a closer look at data integrity industry wide.
Soln: SmartCrys enables manufacturers to conform to data integrity expectations by ensuring mfg processes records for data (generation, analytics and storage) are accurate, complete, legible, attributable, intact and maintained within their original context.
Pain Point #3. Patients are experiencing a rapidly increasing frequency of drug shortages. Better process understanding will lead to faster to market products and a more reliable, predictable supply chain.
Soln: SmartCrys will enhance process understanding and control, rapidly reducing the frequency of drug shortages.
IMPORTANT FOR SOCIETY
Equipping the EU industry with SmartCrys will enable API manufacturers to: a) safeguard product quality and safety in line with cGMP's b) increase process efficiencies, c) reduce costs, d) increase production throughput, e) facilitate quicker new product development.
OVERALL OBJECTIVES
The main objective of this project was to finalize the development of the SmartCrys advanced processing technology and facilitate a wide deployment across Europe and the rest of the world.
PAT are typically used in laboratory-scale reactors such as 1L to 20L capacity. SmartCrys focused on developing technology that could be used in lab-scale and in industrial-scale reactors of various sizes.
The main basic platform for the SmartCrys project is a ‘Crystallizer’ (Syrris), ‘Thermostat’(Heidolp) and ‘overhead stirrer’(Julabo).The PAT consisted of a Wasatch Raman spectrophotometer & probe and Thermoscientific FTIR.
The OPC interface soln facilitates the collection and transmission of data for RT monitoring and control. The main components of SmartCrys: PAT analyser suite, Data Integration Engine, Process Controller, Integrated Control System, Big Data Cloud Storage and Mfg Intelligence Dashboard.
AI/machine learning techniques are implemented in developing the process control model. In-house developed software integrates the data from the overhead stirrers, thermocouple and PAT tools using the ICS.
The control objectives enable the implementation of a product engineering approach to control the crystallization process to directly achieve the desired final product quality. The SmartCrys control strategy is shown in image "Control Strategy Flow chart"
The SmartCrys system allows the user to access the software in offline and online mode. The user can open the finished experiment at any time to track the changes and to retrieve the data to compare with any other experiment.
SmartCrys is designed to control the critical quality attributes of the crystallization process. It has the capability to monitor and control the crystallization process. It is designed to simplify the design of experiment, execution of the experimental design connecting the PAT tools to monitor and retrieve the spectral information and performs the chemometric analysis to understand the process.
Dissemination activities were mainly recorded on the SmartCrys web site. The “NEWS” section of the web site was used as the main mechanism on the page to communicate activities to the general public. This section was kept updated with conferences, workshops, publications and tradeshows that Innopharma were attending. Activities were documented on a month-by-month basis to unsure updated content was posted and to give clear visibility where potential customers could meet with us.
However, due to the Covid 19 worldwide pandemic breakout in March 2020 work practices across the world changed. At first conferences, tradeshows etc were cancelled. Later in 2020/2021 some virtual conferences were held and Innopharma attended virtually, as appropriate.
Due to the covid restrictions it was not possible for our target audience to travel for demonstrations. Like many organisations Innopharma had to relook at its current practices and determine how best to meet potential customers for the SmartCrys technology. With that in mind Innopharma developed a platform to deliver virtual demonstrations of the SmartCrys Technology. This consisted of the hardware and software required to broadcast a live interactive event.
Publications were also linked to the News section on the website, in order to gain greater attention and to reach a greater audience than through the journal’s readership alone.
Many PAT solutions in the crystallisation field enable monitoring of a crystallisation process. However these PAT instruments are neither linked to each other or to the control mechanism of the reactor vessels.
SmartCrys advances the current state of the art solutions, by offering a vertically integrated all in one solution that meets the needs of industry and the regulators. SmartCrys offers a holistic solution including the components needed to control a manufacturing process. This includes integrated chemometrics software, transfer big data from multiple streams and types into knowledge and subsequently into closed loop control of crystallisation processes, incorporates PAT information with soft sensor data and a control model to control crystallisation processes. It is a fully integrated solution that combines in-line analysis and cloud analysis. It automatically aggregates, contextualises, analyses, and distributes data via visualization tools.
In terms of environmental benefits, a reduction in fossil energy use (of up to 30%) can be obtained via optimum process conditions and as a reduction in primary RM use of up to 20% can be achieved through: i) reducing over-processing ii) enhancing efficiency iii) minimising waste.
Value for money analysis
Following engagement with our existing customer base, as well as meeting the regulators expectations, it is estimated that financial savings will be realised both through elimination of lab analysis time and by reduced mfg cycle time. Per annum savings would be greater than €600k for a typical mfg facility with circa 30 batches manufactured per year.
Crystallisation Process Dashboard
System Options
Hardware
FTIR, Raman spectrum, temperature, and concentration profiles during the process of crystallization
Control Strategy