Final Report Summary - PATOV (Process Analytical Technology Unit for Online Verification of the CIP Process in the Pharmaceutical Industry)
Executive Summary:
The Consortium behind this project - a group of European SMEs with expertise in process cleaning and cleaning validation together with an end user and two research organizations - wish to address a major market opportunity in the supply of a process analytical technology (PAT) compliant unit for online verification of clean-in-place (CIP) processes used in the pharmaceutical industry. The Consortium has developed an innovative online total organic carbon (TOC) compatible analytical unit based on a new continuous sampling device, an optimized cleaning fluid recovery process with an effective gas-liquid separation system and a new and innovative laser based infrared (IR) absorption technique. This PAT/CIP device enables a continuous verification of the cleaning cycles of pharmaceutical process equipment (tanks, pipe systems etc.), the device allows integration with existing CIP equipment in accordance with European Hygienic Engineering & Design Group (EHEDG) standards. In fact, this unit allows CIP equipment to be PAT compliant, which promotes a modal shift from sporadic laboratory testing of cleanliness (relying on validated processes) to continuous, in situ verification of every cleaning cycle in the end-user pharmaceutical industry. This is in line with EFSA (European Food Safety Authority) and FDA (U.S. Food and Drug Administration) initiatives for future verification methods for the industry. The participating SME partners have increased their competitiveness through this new and innovative technology. An increase of product safety against potentially hazardous contamination from comprised cleaning cycles is one of the major drivers for the pharmaceutical and food processing industry. Cost and downtime reduction and improvement of environmental issues by reducing water consumption for cleaning and derived waste water problems are further advantages. This new technology has improved the competitive situation for the whole European group of SMEs providing CIP solutions and cleaning validations to the pharmaceutical industry. Moreover, it has the potential for improving the competitive situation for lower added-value, sanitary industries with demands for hygienic standards like the food processing industry and breweries. Additional applications of the device have started to become in focus – because of the near-real-time availability of concentration information the device allows the online monitoring and control of biochemical and bio-pharmaceutical production processes – following proper substrate dosing as well as the evolvement of products during the process in dilute aqueous systems.
Project Context and Objectives:
Project Motivation and Idea:
The PATOV consortium, a group of European SMEs with expertise in process cleaning and cleaning validation together with an end user and two research organizations - have addressed a major market opportunity in the supply of a Process Analytical Technology (PAT) compliant unit for online verification of Clean-in-Place (CIP) processes used in the pharmaceutical industry.
Specifically, the Consortium has developed an innovative in-situ Total Organic Carbon (TOC) compatible analytical unit based on a new continuous sampling device in combination with an alternative infrared laser based contaminant concentration measurement. This PAT/CIP device has proved to enable a continuous verification of the cleaning cycles of pharmaceutical process equipment (tanks, pipe systems etc.), the device allows integration with existing CIP equipment in accordance with European Hygienic Engineering & Design Group (EHEDG) standards. In fact, the developed unit can be easily process integrated and thus enables CIP equipment to be PAT compliant, which promotes a modal shift from sporadic laboratory testing of cleanliness (relying on validated processes) to continuous, in-situ verification of every cleaning cycle in the end-user pharmaceutical industry. This is in line with EFSA (European Food Safety Authority) and FDA (US Food and Drug Administration) initiatives for future verification methods for the industry.
The PATOV project developments have contributed to the competitiveness of the participating SME partners by providing them with an innovative technology that has major drivers for the pharmaceutical and food processing industry. The technology – if process integrated - significantly increases product safety against potentially hazardous contamination from comprised cleaning cycles in pharmaceutical and food production, it decreases production costs and downtime, and improves the environmental issue of water consumption for cleaning and derived waste water problems. This new technology has three major application fields – as add-on to existing CIP solutions and cleaning validation in the pharmaceutical industry, as fully integrated part of CIP solutions designed, manufactured and serviced by SME partners of the project consortium, as an add-on or replacement to in-situ cleaning procedure control in sanitary industries with increasing demands for hygienic standards like the food processing, pet food processing industries, breweries and diary industries.
Project Concept:
CIP equipment provides water for injection (WFI) along with cleaning agents at pre-determined temperatures and pressures for cleaning production equipment in pharmaceutical or food production industry. To conform to high level cleaning regulations, preconfigured, longer than necessary cleaning cycles are followed, which leads to tremendous waste of water and cleaning agents. This is followed by laboratory testing of residual samples from the vessels to determine whether further cleaning is required or the production process can resume. This results in long periods of process downtime, while the laboratory results are awaited, up to several days in some instances.
The developed PATOV device automates the cleaning validation procedures and thereby reduces cleaning costs and process downtime while at the same time providing more analytical information to the client. The critical challenges in the project were related to efficient continuous sampling and the separation of the liquid component from the returned WFI so that it can be fed into commercially available analyzers. The samples should provide a representative contamination information of the cleaning effluents. However, adequate technologies did not exist for real time analyzing of all possible CIP process steps including the recycling step with TOC varying from >10000 ppm down to <1 ppm. Furthermore, commercially available analyzers usually require several minutes to provide reliable results when the conditions change substantially between measurements. This is the reason, despite the significant potential for efficiency improvements, why manual cleaning validation tests are still being carried out in laboratories. While TOC remains the most critical measurement for cleaning validation, once the liquid phase is separated, different analyzers can be used for further analysis as desired by the end user and depending on the process being cleaned. Indeed, nowadays online TOC analyzers are eligible for validation of the final rinse, but not for validation of the entire cleaning procedure. For this reason, the selection and adaptation of a new analytical technology based on infrared spectroscopy was clearly promising and was therefore pursued intensively. After careful evaluation a mid-IR laser absorption technology based on an External Cavity-Quantum Cascade Laser (EC-QCL) was introduced with the potential for a real online monitoring where data can be provided with a time resolution down to one second.
Through development and launch of the PAT/CIP cleaning validation system, the pharmaceutical companies as end-users can now benefit from reduced processing costs and improved products. The public can benefit by receiving pure products at reasonable prices, and the reduced use of water for injection (WFI) in the cleaning processes will benefit the environment. The project has aimed not only at the pharmaceutical industry as end-users but also at current CIP providers to offer them a better solution. These CIP providers thus benefit from PATOV by incorporating the innovative in-situ analytical unit into their current CIP products.
The overall objective of PATOV has been to develop PAT compliant CIP equipment that enables:
1. Knowledge generation on optimal CIP designs and efficient cleaning fluid recovery
2. Sampling system for the continuous extraction of usable samples for TOC measurements or other suitable analyzers.
3. Development of a separation unit where the phases can be instantly separated to obtain a clean liquid sample that can be fed into analyzers and development of an alternative analyzer based on mid-IR laser absorption technology using an External Cavity-Quantum Cascade Laser (EC-QCL) as light source.
4. Integration of the entire system into a single unit according to EHEDG design to develop a marketable product that can be easily integrated into pharmaceutical and food processing units.
5. A proof of concept and demonstration of the system under production conditions at a pharmaceutical company, thus providing practical experience and an information basis for further developments and a commercialization of the developed system.
Project Results:
The main innovative achievement of the PATOV project has been the successful demonstration of an online analytical technology implementation based on QCL technology capable of indicating cleanliness of (bio-) pharmaceutical process equipment, that may become comparable to the standard off line TOC measurement, and thus support a PAT based solution to real time equipment cleaning and release for subsequent batches.
Key results of the first project period involve the definition of typical (base case) CIP process and equipment including CIP cleaning procedures and cleaning fluid balances as applied in pharmaceutical and biotechnological processes. Online analytical technologies for cleaning fluid analysis have been evaluated and pros and cons as well as alternatives have been reported. Based on the gathered information, strategies have been developed in the second period of the project to obtain data for cleaning fluid recovery/balance. An experimental CIP plant was configured according to the defined base case to optimize the process equipment and for testing purposes. Furthermore, best practice recommendations for the CIP process have been compiled. The design of a sampling device and the selection of suitable sampling positions for the base case CIP process have been performed using computational fluid dynamics (CFD) and best practice recommendations have been derived. Hygienic design standards have been evaluated. A 3D-CAD design and P&I diagrams of the experimental CIP plant including sampling and degassing has been made available for the Consortium and the welding and construction of this equipment has been finished. Material properties, fluid flow rates and relevant parameters of the CIP process have been identified and possibilities for the application of an alternative analytical technology have been investigated. Preliminary test series of various concentrations of reference molecules with this alternative technology have given promising results. Subsequently, a prototype (PATOV unit) has been developed and successfully tested in laboratory tests as well as in field operational tests. Laboratory tests have been conducted using the experimental CIP plant. For field operational tests a simplified version has been adapted. The contamination of the CIP process water can be measured with a time resolution down to one second. The retention time of contaminations from the CIP plant to the PATOV unit was minimized to <10 s by the design of an optimized sampling system. The TOC can be detected within the short timelines mentioned for single contaminants down to a concentration of e.g. 20 ppm for glycerol. Other model contaminants have been evaluated as well, such as xanthan and proteins extracted from potato starch production.. The newly developed PATOV unit offers quasi-continuous measurements with time resolutions down to one second. Bearing in mind that the time delay caused by the sampling system is in the order of 10 s, the PATOV unit enables online monitoring of CIP processes. The PATOV unit was successfully applied to experimental CIP process equipment. Calibration for glycerol was conducted with high linearity down to a detection limit of 20 ppm. First laboratory experiments and field operational tests show promising results. Valuable process information was gathered which could be used to significantly optimize the cleaning procedures resulting in increased process efficiency and quality. It has to be emphasized that the sampling position must be well chosen and short connection lines to the PATOV unit have to be established. The findings have been compiled into a design guide. Also, experimental data with regard to IR-QCL / TOC comparison have to be considered as preliminary. TOC measurement of off-line samples still show deviations - partly due to a difficult sampling situation at the plant site, therefore validation of the on-line data will be a very important target for future investigations and a standard application of the PATOV device. Extension of the analytical device for application to proteins was already shown and based on the promising results continued after the end of the project by manufacturing a QCL light source for the protein spectral region through scientific partner Vienna University of Technology. Improving the detection of lower concentrations and calibrating for other model contaminants and real-world contaminations will be objectives for further investigations. Future applications of the PATOV unit may also involve CIP of food processing, pet food processing plants as well as breweries and diary industries. Further target applications have already been proposed: chemical and biotechnological industries where the PATOV device can play an important role set point control or model predictive control applications.
Potential Impact:
The PATOV project has demonstrated that it most likely is possible to develop and implement process analytical technology to equipment cleaning processes in the pharmaceutical and biopharmaceutical industries.
Other industries, where this technology may be of interest, are areas such as food and beverage industries, where the product safety relies on the cleanliness of manufacturing equipment, and large volumes of fluids containing organic matter are handled.
Despite current trends to implement disposable process equipment in more and more manufacturing plants, a large number of pharmaceutical and biopharmaceutical manufacturing facilities are and will continue to be based on reusable equipment. Especially for routine manufacturing of approved (bio-) pharmaceuticals, where large scale cultivation and microbial fermentation steps are involved – multiple use and cleaned equipment will continue to be the state of the art in the foreseeable future.
In (bio-) pharmaceutical plants, the documentation of cleaning is of the utmost importance. The inner surfaces of the equipment that are in product contact need to be verified clean. Strict limits are set for maximum allowable carry-over of active material from one batch to the next - both of the same product and between batches of different products.
The cleaning processes typically employed in the industry depend on use of large amounts of water and energy as well as considerable amounts of chemicals such as caustic, acidic and oxidizing reagents. All of these have a considerable environmental impact and some further a substantial climate footprint.
With the detection technology applied in the PATOV project, it seems likely that it will be possible to stop the cleaning process steps when the equipment is actually clean and avoid the excess length of the cleaning cycle steps hitherto employed to be absolutely certain that any residue of the previous batch was removed. As opposed to the previously employed technology (online conductivity supplemented with offline TOC + TOC in swab samples from cleaned surfaces) it is now possible to obtain an online indication of the TOC in the rinse liquids.
Following the recent trends in Pharmaceutical Process Technology and the cGMP (Current Good Manufacturing Practice) expectations and requirements to process validation, PAT and QbD (Quality by Design) – which also apply to Cleaning Processes – the possibility also opens up to validate cleaning cycles based on online results, and thus release the cleaned equipment for the next batch - even for manufacture of commercial pharmaceutical and biopharmaceutical products.
With the final results, a prototype of an online sampling, separation and real-time analytical measurement device has been made available that allows for the monitoring and further optimization of state-of-the-art cleaning in process (CIP) system through: 1. Knowledge of effluent contamination during CIP process. 2. Estimation and prognosis of cleaning time and cleaning agent needs and consumption. 3. Process control toolbox for the operation of the CIP unit. Additionally, concepts for the proper placement of optimal cleaning fluid sampling point, a concept for cleaning fluid balancing and concepts for the integration of the entire system into a unit according to EHEDG design will be available to develop a marketable product that can be easily integrated into pharmaceutical and food processing units are expected.
Societal and policy objectives:
The societal and policy effects of PATOV are primarily related to securing health and to lowering waste water and energy savings from WFI production through the use of embedded monitoring technology. Accordingly, the primary societal and political objectives are the following: 1. To contribute to the objectives of the Lisbon Strategy for Growth and Jobs by the creation of jobs in the participating countries and beyond through distributors and vendors based on significant additional turnover for the SME partners 5 years post project. 2. To reduce energy consumption in the pharmaceutical companies, in breweries, and in the food industry and its equivalent to saved CO2 emissions through reduction in WFI production and usage of chemicals. As could be shown, the reduction potential in water savings, savings of chemicals and savings in cleaning time which is down-time for the production is in excess of 10% for each of the three aspects.
List of all scientific (peer reviewed) publications relating to the foreground
- 16th PRES (Conference on Process Integration, Modelling and Optimisation for Energy Saving and Pollution Reduction), September 29 – October 2, 2013, Rhodes, Greece (peer reviewed paper, accepted on April 24, 2013)
List of other dissemination activities
- ACHEMA, June 18 – 22, Frankfurt, Germany (PDF Presentation)
- International Quantum Cascade Lasers School & Workshop 2012, September 2 – 6, 2012, Baden, Austria (Poster Presentation)
- 200th IRDG (Infrared and Raman Discussion Group) Meeting, December 20, 2012, London, UK (Poster Presentation)
- Project presentation on website: www.ecoweb.info
- First internal workshop, June 14, 2012, TUW, Vienna, Austria
- Second internal workshop, January 15, 2013, CMC, Copenhagen, Denmark
List of Websites:
Public website:
www.patov.eu
Contact details:
Dr. Michael Harasek
Vienna University of Technology
Getreidemarkt 9/166
1060 Vienna, Austria
+43 1 58801 166202
michael.harasek@tuwien.ac.at
