Proceedings of the 6th International Conference on Process Systems Engineering (PSE ASIA) 25 - 27 June 2013, Kuala Lumpur.

Applying Process Systems Engineering for Continuous Improvement in Pharmaceutical Production
Hirokazu Sugiyamaa,b, Sandra Schinzela, Georg Müllerc, Rainer Schmidta

Pharma Technical Operations Bioloigcs, F. Hoffmann-La Roche, Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland b Department of Chemical System Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8656 Tokyo, Japan c Site Engineering Basel/Kaiseraugst, F. Hoffmann-La Roche, Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland

In the field of process systems engineering (PSE), pharmaceutical industry is recognized as one of the future research targets [Reklaitis, 2007], and more intensive work is being desired. With the aim of contributing to this research movement, this paper showcases industrial application of PSE and related methods for improving pharmaceutial production processes. The target here is a Roche new manufacturing facility of Parenterals (i.e., injectable drug products) in Kaiseraugst called PKau, which started commercial operations in 2012. Already during the facility start-up, we have been applying PSE methods in improving PKau production processes considering quality, finance as well as environment in a continuous manner. Three case studies are presented in this paper: (1) reduction of product losses by applying simple mass flow analysis (2) mitigating product quality using risk assessment tools, and (3) improving energy consumption of the facility using Sanky diagram and multiobjective optimization techniques. Keywords: Pharmaceutical production, Parenterals, energy efficiency, risk analysis, industrial case study

1. Introduction
Production processes of pharmaceuticals are facing wide range of pressures. Authorities are constantly raising the level of GMP (Good Manufacturing Practice) requirements, and at the same time, healthcare reformations are requesting higher cost-effectiveness. In order to cope with such situation, companies need to apply various methods not only from pharmaceutical sciences but also from other fields in an interdisciplinary manner. Here, the strength of PSE can be explored for continually improving pharmaceutical processes, which discipline was originally developed for chemical processes and not yet fully known in pharmaceutical industry. On the side of academia, pharma industry is recognized as one of the future expansion targets of PSE (Reklaitis, 2007). Up to now, several industrial case studies have been presented with addressing the usefulness of process modeling and statistical process control (e.g., Dassau et al., 2006, Dünnebier, 2008). However, more work needs to be done for establishing PSE as a support tool of continuous improvement in pharmaceutical industry.

Applying Process Systems Engineering for Continuous Improvement in Pharmaceutical Production 601 Figure 1 Parenterals production Kaiseraugst in Roche. The values of m can be obtained by converting data in MES to g-API equivalent. stored in different units of [L] or [#vial]. 2.e. In the last step. The target here is a new Roche manufacturing factory of Parenterals (or injectables) in Kaiseraugst. Isolator technology shown in Figure 1 (c) is extensively applied in order to avoid contamination of injectable products. As can be seen in Figure 1 (a).g. we present three case studies of process improvement using PSE and related methods. this indicator was applied to the 17 validation batches produced at that time point. and the overall f was obtained as shown in Figure 2 (a). which helps management to focus on the most relevant ones for prevention. (b) three product forms to be produced and (c) filling line of liquid vials with isolator technology. samples for quality control taken in the filling step. excipients and Water for Injection (WFI). dead volume in hardware. Switzerland termed PKau. In this way. This facility. produces high-value biologics products aseptically in the forms of liquid vials. e. shown in Figure 1 (a). there are various causes of product losses. The second highest is the product samples taken for product release testing and various analyses for validation purposes. In this paper. Switzerland: (a) exterior of the facility. contribution of different causes to the overall loss has become comparable. 100% visual inspection is performed to sort out defectives from good items which are sent to the adjacent packaging facility. The first is to compound the product solution by mixing defined amounts of API. prefilled syringes and lyophilized vials as depicted in (b). Secondly the solution is filled into primary packaging materials such as glass vials. scratch on vial outer surface. 2nd Order Heading The aim of the first case study was to reduce losses of liquid vial products in PKau. however. i. In these three steps. and are thus rejected in visual inspection. lyophilized if needed. which consists of the following three batch process steps. and closed with rubber closures and caps in a sterile environment. An expert team then created a indicator f for measuring contribution of individual causes to the overall loss over batches i: (1) where is the API mass [g] in the non-product output at step a in category b. the largest contribution is minor defect or items not fulfilling the required level of cosmetic appearance. and aseptic interventions are performed using isolator hand gloves. e. The third . or products rejected due to cosmetic defects in visual inspection.g. As an implementation. Case Study 1: Product Loss Reduction 2.1. samples due to GMP requirements and loss due to poor operations. These data are accessible in a modern data management system termed Manufacturing Execution System (MES).

management decided to provide resources for improving the first and third causes and not to focus on the second. the productcontacting parts of the system. and to declare the takts afterwards as regular product. the obtained Cpk was larger than 2. since the detail of reducing cosmetic defects in the PKau processes is to be reported in a separate paper (Sugiyama and Schmidt. The robustness of the result has been quantified using process capability index Cpk: (2) where and represent estimates of sample mean and standard deviations. Figure 2 Results obtained for reducing product losses: (a) contribution of different loss causes to the overall loss amount of 17 validation batches (b) concentration of a product during early phase of machine pre-run. various product properties were measured during the pre-run. At the sterile filling of liquid vials. such as product filter. because many samples were taken puprposefully in the validation batches. In this work. which represents a process that has at least six standard deviation ranges between mean and either of USL or LSL. During the early start-up. Therefore in this case. which corresponds to around 90% reduction of the pre-run discharge. are sterilized with highly purified steam and dried before the solution is introduced.602 H. management decided to discard only the takts analyzed. pipes. Figure 2 (b) shows the product concentration of vials in the early pre-run phase in comparison with the upper and lower specification limits (USL and LSL). In this case. we present the improvement work done on the third cause. a potential risk was identified that a tiny amount of saturated steam could influence on the product concentration. The product concentration after the analyzed takts can be expected to be even more robust than the result in Figure 2 (b). buffer tank and filling needles. and thus the vials filled in the first takts have been discarded as machine pre-run during validation batch production. as was seen in Figure 2 (a). 2013). Sugiyama et al is the product solution losses during the machine pre-run phase before the filling process starts. Parallel to the efforts to prevent this risk from the source. . in order to determine the degree of potential dilution. In the case of Figure 2 (b).

8. which is classified as high risk according to the company criteria. there are various sources of potential errors. 4. 6. Generally in pharmaceutical production. Table 1 shows an example of an FMEA study on aseptic intervention in the filling isolator. so-called failure modes. 8. human errors. 10] SOP* in place for controlling hand gloves 4 RPN 240 (high risk) Figure 3 Results obtained for managing product quality risk: (a) number and characterization of failure modes associated with asepctic operations in the filling isolator before and after the improvement (b) example of an improvement . and the socalled Risk Priority Number (RPN) is obtained as follows: RPN = Severity  Probability  Detectability (2) These three parameters are usually evaluated using integer scores such as [2. The obtained RPN is in this case 240. Case Study 2: Managing Product Quality Risks The second example is about managing product quality risks in the operation. 6. 2005]. In an FMEA of a working process.Applying Process Systems Engineering for Continuous Improvement in Pharmaceutical Production 603 3. or potential causes that could lead to unfavorable results. where the hand glove could be damaged by scissors used inside the isolator. which could lead to impact product quality. Each failure mode is then evaluated in terms of severity.. 6. Failure mode Isolator hand gloves damaged by an erroneous use of scissors inside the isolator Severity [2. We applied Failure Mode and Effect Analysis (FMEA). Table 1 Example of an FMEA on aseptic interventions in the filling isolator. *SOP stands for Standard Operating Procedure. 4. 4. 10] In a certain frequency 6 Detectability [2. 10] Product contamination  10 Probability [2. e. 4. are first generated. possibility and detectability. 10] whereas the scoring system depends on the company policy. 6. which is commonly used in quality engineering and also one of the recommended methods from the health authorities [International Conference on Harmonization. 8.g. 8.

and a screening was necessary for narrowing down the alternatives.e. With a focus on these infrastructure processes. In our case. This domination comes from the fact that the study was performed during early start-up phases. almost all options were in a trade-off relation. This step identified two out of four options as Pareto optima. running cost. This hierarchical Sankey diagram helped focusing on the relevant processes. Although this Sankey diagram is based on the data during the start-up phase.. options with high GMP risks were first eliminated. inspection up to product dispatch. For these risks. Case Study 3: Energy Reduction The third example is on the reduction of energy consumption. Figure 3 (a) shows the number of failure modes associated with the aseptic operations during filling. In order to identify relevant processes. and most prominently the Heating. and which will expectedly reduce energy consumption more than 10 % on the GJ basis as shown in Figure 4 (b). each of which contains sub unit-processes in the second level. the initial evaluation has been updated. from material reception through compounding. and Air Conditioning (HVAC) system. For the example in Table 1. more than half of the failure modes were classified as medium or high risk. Ventilation. an expert team was formed to generate various alternatives in reducing energy consumption. filling. This system is of high importance in pharmaceutical manufacturing. Use of FMEA enabled prioritization of the error sources that need to be improved. a Sankey diagram was developed as in Figure 4 (a) for visualizing the different utilities supplied to PKau from the site service. as seen in Figure 3 (b). Pareto optima. which is becoming increasingly important in pharmaceutical industry nowadays. Production systems of utilities in PKau are also high contributors such as production of highly purified steam or WFI. These options were then evaluated with six simple evaluation indicators: energy saving potential. which were recommended for implementation.e. the scissors in the isolator were first rounded. which in this case was the infrastructure part. which is one of the most critical operations from the entire processes. GMP risks. which resulted in elimination of high risks and increase of low risk modes. processes related to production and ones associated with infrastructure are first differentiated.604 H. safety impact and workers’ comfort. and then removed by modifying the operations that required scissors. various potential risks have been identified in the entire PKau processes. One was to introduce flexible recirculation in the air conditioning system. yielding more than ten ideas. i. as seen in Figure 3 (a). which are used for cleaning and sterilizing production equipment as well as for production itself. . After implementing this type of improvements. and the process know-how was still under development. and then the remaining four Pareto optimal options were selected for further investigation. various counter measures have been implemented in a step-by-step manner. Here. three alternatives including these two Pareto optima were realized. The second evaluation was then performed using Net Present Value (NPV) and FMEA for covering the financial benefits and all associated risks in a detailed manner. In the initial evaluation. which has low potential in both NPV and risks.. which has high NPV potential with a manageable risk. In this multiobjective evaluation. investment. 4. Sugiyama et al Using FMEA. a sensitivity analysis revealed that even after the ramp up the dominance of infrastructure will remain. i. and guided continuous reduction of quality risks already during the facility start-up. and especially in Parenterals production where the cleanliness of the working place is maintained with a proper air conditioning. In this case study. The other was to avoid unnecessary cooling of WFI through operator training.

Joulia). References E. Conclusions and Outlook PSE and related methods for process simulation and optimization have been playing a central role for the continuous improvement in In Roche Parenterals production in Kaiseraugst. 35-38.S. ICH. V. 943-948 G. quality risks and energy consumption. Chem.. Proceeding of 18th European Symposium on Computer Aided Process Engineering (Ed. it would be helpful to foster more intensive collaboration between industry and academia and knowledge-sharing.making. Dassau. Perspectives on process systems engineering R&D in support of pharmaceutical product/process development and manufacturing. Eng. Schmidt. Sankey diagram and multiobjective optimization were applied in order to improve process performance regarding API yield. Lewin. 2008. Quality risk management. Zadok. Ind. Sugiyama. R. 8299-8309 G. Combining six-sigma with integrated design and control for yield enhancement in bioprocessing. Proceeding of 17th European Symposium on Computer Aided Process Engineering (Ed. Agachi). Moreover. R. mass flow analysis. B. I. 45. V. Dünnebier. Elsevier. Use of simple tools resulted in a large business impact. Troubleshooting and process optimisation by integrating CAPE tools and Six Sigma methodology.ich. Braunschweig and X. FMEA. http://www. submitted to ESCAPE 23 International Conference on Harmonisation (ICH). For demonstrating such usefulness of PSE and related methods in the pharmaceutical Quality/Q9/Step4/Q9_Guideline. Elsevier. H. 2013. Reklaitis. 2007. In the examples above. D. R. 5. the strength of PSE methods was demonstrated especially in supporting more data-based prioritization and more rational decision. 2006. Plesu and P. (2005). Business model of continuous improvement in pharmaceutical production processes. Res.pdf . respectively.Applying Process Systems Engineering for Continuous Improvement in Pharmaceutical Production 605 Figure 4 Results obtained for reducing energy consumption: (a) hierarchical Sankey diagram of PKau processes for identifying improvement opportunities (b) comparison of energy consumption before and after improvements on GJ basis.