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

Periodic Reporting for period 1 - SmartCrys (Advanced intelligence and close-loop control for Crystallisation of API’s (Active Pharmaceutical Ingredients))

Reporting period: 2019-01-01 to 2020-02-29

"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.
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.
The main objective of this project is 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. The current project SmartCrys will focus on developing technology to be used in lab-scale reactors and further develop to use in industrial-scale reactors.
The main basic platform for the SmartCrys project is ‘Crystallizer’, ‘Thermostat’ and ‘overhead stirrer’. A 1L industrial standard vacuum jacketed reactor was acquired from Syrris, overhead stirrer acquired from Heidolph and chiller or temp control unit was acquired from Julabo. The OPC interface soln is to facilitate the collection and transmission of data for RT monitoring and control. This includes the main components of SmartCrys: PAT analyser suite, Data Integration Engine, Process Controller, Integrated Control System, Big Data Cloud Storage and MFG Intelligence Dashboard as shown in Figure 1.
AI/machine learning techniques are implemented in developing a suitable control model in order to control the process automatically. In-house developed software integrates the data from overhead stirrers, thermocouple and PAT tools using the ICS.
The data therefore needs to be reliable and easy to access and the raw data needs to be protected from manipulation, corruption or deletion (21 CFR compliant).
The control objectives such as supersaturation control, distribution shaping control allow the precise tailoring of the shape of the crystal size distribution, which enables the implementation of a product engineering approach to control the crystallization process to directly achieve the desired final product quality.
Another challenge in SmartCrys is associated with sensor limitations. Measurements of both the solution concentration and the crystal size distribution are necessary for effective identification and control.
ATR FTIR instruments were shortlisted to monitor solution conc, as a measure of nucleation and growth rates - highly useful for feedback control.
Crystal-Vis is a crystal growth monitoring technology that applies real-time analysis of video microscopy images to monitor particle size in situ. The design of the Crystal-Vis system is to be revised for higher resolution and to fit inside the inlet ports of the crystallisation reactor. The design of the crystal visualisation method sensor will be revised for higher res (~0.1 μm) and to fit inside the inlet ports of the crystallisation reactor (with an outer diameter of 20 mm).
Raman scattering has much narrower peaks than NIR and the shape of the peaks is more sensitive to changes in the analyte so Raman Spectroscopy was considered to be more appropriate for use in the SmartCrys project.
A simple crystallisation rxn, typical of those used in the Pharma industry, was monitored using different Raman Spectrometers and the spectral data was recorded and analysed using PCA. The Wasatch Photonics Raman Spectrometer with integrated 785nm laser and Performance ball probe, thermoelectric cooling was selected as appropriate for the SmartCrys PAT suite (see Figure 2).
Image analysis algorithms were developed to extract information on nucleation and crystal growth from polarized light micrographs.
The SmartCrys home page as shown in Figure 3 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.
Currently 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 all of 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 physical, chemical 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.
Figure 2: Experimental setup of Wasatch Raman
Figure 3: SmartCrys home page
Figure 1: Overview of SmartCrys