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- Fast X-Ray Tomography Techniques : ready for new Pharmaceutical Applications ?
Fast X-Ray Tomography Techniques : ready for new Pharmaceutical Applications ?
Pharmaceutical industry is willing to enhance product quality and manufacturing effciency using modern technologies. Fast X-Ray Tomography Technique can be one of these, as it combines accuracy detection of and complex system reconstruction.
CyXplus, acknowledged to be a major player in the Non Destructive Technique industry, continuously works at supplying the most efficient inspection equipment and software to demanding manufacturing industries. Tire Industry, Aerospace, Automotive, Oil & Gas, are familiar with Non Destructive Techniques (NDT) implementation. More recently, Pharmaceutical Industry has also started to use NDT systems.
For the last decade, CyXplus has been constantly developing and improving 3D X-ray tomography techniques dedicated to various industrial applications, and especially by designing the CyXCT range of X-ray CT equipment and software.
2. How Inspection Techniques have been transformed ?
In the past, various vision solutions for the inline inspection of syringes have been implemented, checking the presence of the parts composing the device (piston, needle,) and liquid for pre-filled syringes for instance.
As vision solutions give limited results, X-ray technic has been implemented.
X-Ray brings the advantage of providing internal information, whereas vision will often be limited by the primary packaging. It is a relevant mean of inspection for various medical devices.
Thus, InLine 2D X-ray equipment has been designed to perform inspection of injection or dispensing devices.
Yet, for some objects, the 2-dimensional approach of vision and X-ray methods cannot prevent for not seeing a defect under certain specific angles.
For example, for glass syringes, a torsion defect of the needle can be hidden if it is in the X-ray source/detector axis.
A crack can be found on a glass syringe or ampoule, but not detected when it is tangential, and parallel to the X-ray axis.
Therefore in such cases, a 3-dimensional assessment of the object is necessary. A solution is to apply and transpose Computed Tomography techniques to this inspection case so as to give more information on the inspected object.
3. What is Tomography ?
Computed Tomography imaging (X-ray CT) consists of directing X-rays onto an object from multiple orientations and measuring the decrease in intensity along a series of linear paths(1)(2)(3). A specific algorithm – a reconstruction algorithm – is then used to reconstruct the distribution of X-ray attenuation in the volume being imaged, and to create a virtual 3D representation of the object.
In the case of an inspection equipment, Computed Tomography requires to rotate the object or to have the X-ray source and the detector that turn around it.
This rotation is necessary to acquire hundreds of 2D radiographies, in order to create the 3D volume.
The given result is a detailed picture of the Tomography inspected object, so as to be able to detect any default with a high level of accuracy.
Examples of view are given on picture below.
The implementation of Computed Tomography in a production line is thus to be considered, but remains technically complex due to the necessity of manipulating and rotating the object in a very short time, and, depending on the object to inspect, quite expensive.
Working within these constraints, CyXplus proposed to inspect a large number of units at the same time, instead of performing a tomography on a single object inline.
4. Current Application for Pharmaceutical Industry : syringe inspection
Regarding the inspection of syringes, CyXplus proposed to inspect a nest of syringes at once.
This approach led CyXplus to use the architecture of an existing model in its CyXCT computed tomography range of equipment, and to adapt the equipment to accept the repeatable insertion of a syringe nest for inspection.
The building blocks used to match the application were:
• CyXCT+160 X-ray/Computed tomography equipment, and its architecture,
• CyXray acquisition software,
• CyXCT tomography reconstruction software + dedicated module for control.
As a standard system, CyXCT+160 enables ultrafast reconstruction on small objects, as a result of the ultra-fast implementation on multiple GPU boards, and on-the-fly reconstruction module in CyXCT software.
Several adaptations were needed to fit with the application needs.
Despite the fact it requires a manual loading, the application is in the production process, « at-line » instead of « in-line », where cycle time requirements are very demanding.
The inspection session is organized by batches of nests or tubs. Each batch is associated with a dedicated recipe (with its dedicated inspection parameters), and the machine inspects the tubs one after the other.
In this configuration, all the syringes present in a given tub are inspected at the same time.
Thanks to the database architecture, a production quality analysis can be done in real time. Automatic reports with statistical indicators can be generated to show a production problem.
Thanks to its ultrafast CT architecture, the CyXCT+160 is able to inspect an object of 100 cm3, with a 100μm resolution in less than 30 seconds.
In the present syringe inspection application, the CyXCT+160 system needs 80 seconds for the inspection of a nest, with 2000 controls performed and at a 100μm resolution.
Cycle time is one thing, but the accuracy of the inspection is essential. For the syringe inspection application, CyXplus has developed a dedicated defect detection module for CyXCT software. This detection module checks different type of default :
• Needle angle defect – number of defectives tests per tub.
• Cap deformation defect – number of defectives tests per tub.
• Distance needle/cap defect – number of defectives tests per tub. • Cap insert defect – number of defectives tests per tub.
• Syringe presence defect – number of defectives tests per tub.
• Needle presence defect – number of defectives tests per tub.
• Closure presence defect – number of defectives tests per tub.
The batches, objects and detection information are consolidated into 3 databases to insure the conformity with the 21 CFR Part 11(4):
• Database with control results.
• Database allowing to perform diagnostic.
• Database with alarms and events recording.
Thus, the reconstruction and signal processing algorithms enable to accurately detect, localize and quantify defects, in a cycle time compatible with value expected for a production line.
Inspection reports are saved in the database according to the 21CFR part 11 standard(4), and also in pdf format. The production reports are edited with the localization of the defective syringes for each tub.
These results show that X-Ray CT is a very interesting technique for this application (syringe inspection), due to its performance.
5. Ready to go further ?
The application of X-Ray CT for syringe inspection gives us an insight of the potential other applications in the pharmaceutical Industry : this technology could be used to improve quality of detection, and also to get fully digital report.
Improve quality of detection
As X-Ray CT allows to detect, localize and quantify defects, in a cycle time compatible with value expected for a production line, it constitutes a step change in the assessment process of the quality of the products. This ability to detect and quantify defaults with high accuracy could be used either to inspect objects, or to help for root cause investigation in case of troubleshooting.
Evolution of EU GMP Annex 1(5) should lead industrials to pay deep attention to default detection (paragraph 8.26) « All filled containers of parenteral products should be inspected individually for extraneous contamination or other defects (…) Different defect types should be categorized and batch performance analyzed. » The accuracy of detection is also crucial « Where automated methods of inspection are used, the process should be validated to detect known defects with sensitivity equal to or better than manual inspection methods and the performance of the equipment checked prior to start up and at regular intervals ».
X-ray CT is also definitively a complete field of the process that becomes fully digitized from image acquisition to results database, giving to a production line the possibility of having connected installations and a direct link between information and real time product quality control.
6. New Pharmaceutical Applications
The pharmaceutical industry is adopting emerging technologies. Modernize manufacturing, learn from others (like aerospace or electronic) are part of pharmaceutical industry strategy to go further in digital transformation and to improve product quality and manufacturing efficiency.
X-ray CT can hence be considered as a relevant option for the in-line non-destructive testing of medical devices, and an important milestone of an end to end INDUSTRY 4.0 manufacturing process.
Based on this, other applications can be derived with different configurations and implementation, in order to inspect other medical devices at the end of production line.
For instance, instead of loading a nest or group of products, a robotized arm can be programmed to automatically load and unload the devices to be inspected.
Complex assembly, in-line inspection of specific Drug Product, , Inspection of aseptic connectors and/or assembly could also be some new applications for X-Ray CT.
What’s more, not only we may think of other inspection applications in the production area, but also a versatile equipment can be used for troubleshooting, or prototyping (R&D) or expertise. For example, reconstruction of the volume of a specific part of a device or object. The 3D volume can be explored and cross-section can be extracted from tomography. The reconstructed volume can also be imported into a third-party software for 3D expertise.
CyXplus X-Ray CT is a mature technique already used for pharmaceutical applications (syringe inspection). It can offer new opportunities for the Pharmaceutical Industry: opportunity to inspect complex assembly with high accuracy, opportunity to go further into digital transformation, part of Industry 4.0.
Estelle DARNON – TECHNIP
Estelle Darnon is a senior pharmaceutical process engineer at TechnipFMC, in charge of pharmaceutical regulatory compliance and facility design for TechnipFMC Life sciences projects.
Frédéric ISNARD – CYXPLUS
Frédéric Isnard held several business and management positions in the industry in the past 25 years, and has been heading CyXplus for ten years.
NDT : Non-destructive Testing
R&D : Research and Development
X-Ray CT : X-ray Computed Tomography
GMP : Good Manufacturing Practice
(1) Industrial X-Ray Computed Tomography 2018 S Carmignato, W Dewulf, R Leach (Eds.)
(2) Industrial application of computed tomography CIRP Annals Vol 63, Issue 2, 2014 pages 655-677 L.De Chiffre, S. Carmignato, J.-P. Kruth, R.Schmitt, A.Weckenmann
(3) Digital Image Processing 3rd edition 2008 Rafael C. Gonzalez, Richard E. Woods
(4) Food and Drug Administration – Code of Federal Regulation CFR, Title 21 Food and Drug, chapter I subchapter A part 11 Electronic records ; Electronic signatures
(5) European Commission. “Annex 1 Consultation Document” https://ec.europa.eu/health/sites/health/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf