Faida Mhenni
email: faida.mhenni@supmeca.fr

Jean-Yves Choley
email: jean-yves.choley@supmeca.fr

Nga Nguyen
email: nga.nguyen@eisti.eu

SysML Safety Profile for Mechatronics

Safety analysis of mechatronic systems is a timeconsuming activity, because of the complexity of these systems that involve different fields of engineering. It is desirable to carry out safety assessment methods as soon as possible in the design process in order to reduce errors, cost and time to market of the system. Our paper addresses this problem by proposing a safety profile that is integrated directly with the modeling elements of the system via SysML, a model-based systems engineering language. Failure modes of each function and each component, their causes, their effects as well as their severity are modeled via stereotypes or tag definitions that extend the existing UML elements. These failure data can be 1) entered directly by systems engineers when possible; and then 2) generated automatically for safety experts' work; and also 3) updated from safety analysis results. Our integrated systems engineering and safety analysis process helps to narrow the gap between these two disciplines by ensuring the consistency in the whole process. A case study with an electromechanical actuator is given to illustrate the process as well as the safety profile.

I. INTRODUCTION

Nowadays systems often have to provide the end-user with more functionality while being confined in a compact volume and being less energy consuming. Mechatronics offers the opportunity to design such smart systems. The complexity of mechatronic systems mainly relies on the merging of very different technologies such as mechanical devices to actuate, embedded software and electronic hardware for command and control purposes, with respect to an appropriate automation strategy. Mechanical parts, electronic components and software routines are on their own error sensitive, thus needing thorough safety studies in order to make them safe and reliable. When it comes to the integration of all these components in a so-called smart mechatronic system, usual safety assessment methods are not self-sufficient and have to be widely extended and supported by new design tools and methodologies [START_REF] Cressent | Dependability analysis activities merged with system engineering, a real case study feedback[END_REF], [START_REF] Mhenni | Safety Analysis Integration in a SysML-Based Complex System Design[END_REF]. Since systems engineering is almost becoming compulsory for designing such complex artificial systems [START_REF] Mhenni | A SysML-based methodology for mechatronic systems architectural design[END_REF], an integrated safety analysis and systems engineering process is our proposal. This means that there is a need to customize the usual systems engineering framework in order to have it adapted for safety expert's activities. The Unified Modeling Language (UML) [4] is a general-purpose modeling language in the field of software engineering, which comes with the ability to be customized using the profiling extension mechanism. Numerous system design activities use UML profiling to have builtin domain-specific functionality available in a dedicated design framework, such as for RTES (Real-Time Embedded Systems) design with MARTE (Modeling and Analysis of Real Time and Embedded systems) or for systems engineering domain with SysML. Thus, our goal is to provide the safety experts and systems engineers with tools and methodologies relying on a domain-specific profile for safety analysis for mechatronics, based on SysML, a widely used systems engineering language.

The paper is organized as follows. Section 2 discusses several famous UML extensions for domain specific applications. Section 3 presents our methodology for the integration of safety analysis in systems engineering process. Section 4 explains the proposed Safety Profile using together with SysML models to support the methodology. An electromechanical actuator example is studied in Section 5 and conclusions are given in the last section.

II. RELATED WORK

As a generic UML extension mechanism, a profile is a collection of stereotypes, stereotype attributes and constraints applied to specific UML modeling elements (classes, activities, ...) in order to customize UML for specific domains and platforms. For this purpose, stereotypes extend UML vocabulary to create new domain-specific modeling elements derived from generic UML ones. Four examples of profile namely SysML, MARTE, Mechatronic UML and UPDM are presented thereafter.

SysML is a profile proposed by OMG (Object Management Group) with INCOSE specifications for systems engineering [5]. It offers new specific diagrams such as Requirement and Parametric diagrams. It also provides modified UML 2.0 diagrams such as Activity diagrams, Block definition diagrams and Internal block diagrams. SysML is now well-known as an efficient systems engineering language, though very few guidelines have been provided by OMG and INCOSE, thus being slowly adopted by potential industrial users. When used with other profiles such as MARTE, this profile can be relevant for mechatronic systems modeling [START_REF] Schäfer | Model-driven development with Mechatronic UML[END_REF].

Replacing the former UML profile for Schedulability, Performance and Time Specification (SPTP), MARTE is the UML 2.0 OMG standard for Real-Time Embedded systems modeling and Analysis (RTEA), dealing with software and hardware aspects. It provides non-functional property modeling such as performance, scheduling; adds time features; defines concepts for software and hardware platform modeling; and provides quantitative analysis [START_REF] Faugere | MARTE: Also a UML profile for AADL[END_REF].

In [START_REF] Iqbal | Experiences of applying UML/MARTE on three industrial projects[END_REF], Zohaib et al. discuss experiences about applying MARTE profile for Real Time Embedded Systems (RTES) design. Three industrial experimentations are explained. The first one deals with architectural modeling and configuration, applied to ICSs (Integrated Control Systems), which are heterogeneous systems-of-systems. In these systems, software and hardware components are integrated to control and monitor physical devices and processes, such as process plants or oil and gas production platforms. The request of the industrial partner (FMC Technologies Inc.) was mainly for capturing software and hardware components interactions, enhancing consistency between software and hardware modeling and, finally, enabling automated configuration and configuration reuse. The second experience deals with model-based robustness testing, using also stereotypes from Robustprofile from Simula Research Laboratory [START_REF] Ali | Modeling robustness behavior using aspect-oriented modeling to support robustness testing of industrial systems[END_REF]. The project aimed at supporting automated, model-based robustness testing of SATURN, a video conferencing system from CISCO Systems Inc. The last experience deals with Testing RTES using MARTE environment models on a large and complex seismic acquisition system with tens of thousands of sensors and actuators in its marine environment (WesternGeco and Tomra). Models were used to generate an environment simulator, test cases, and obtain test oracles.

MARTE is also a UML profile for AADL (Architecture Analysis and Design Language), a Domain-Specific Language (DSL) that deals with the hardware platform and the physical environment of intensive embedded software systems. It can be used to model application tasks and communication architectures, thus allowing modeling and analysis of coupled software and hardware RTES aspects.

Mechatronic UML is a specific profile for mechatronic systems. It is derived from the safety-critical software development domain with the main objective of bringing model-based design, domain testing and simulation, and formal analysis to the mechatronics area [START_REF] Schäfer | Model-driven development with Mechatronic UML[END_REF]. The aim behind this is to guarantee highly safety-critical system properties. The profile restricts the usage of UML to certain types of diagrams and extends these diagrams to be able to model hybrid and self-adaptive systems. The use of formal semantics to model the components allows formal analysis. This profile aims at being more efficient than approaches such as SysML that does not adequately support modeling of time, and MARTE that does not provide the needed architectural abstraction for hardware [START_REF] Schäfer | Model-driven development with Mechatronic UML[END_REF].

The fourth profile is UPDM (Unified Profile for DoDAF/MODAF) [START_REF] Omg | Advancing MBSE via unified profile for DoDAF/MODAF (UPDM)[END_REF]. DoDAF (Department of Defense Architecture Framework, US), MODAF (Ministry of Defense Architecture Framework, UK) and NAF (NATO Architecture Framework) use this profile to define architecture frameworks that are domain specific and define practices for creating, interpreting, analyzing and using architecture descriptions, as described in ISO/IEC/IEEE 42010 [START_REF]Systems and software engineering -Architecture description[END_REF].

Concerning the integration of safety analysis and systems engineering, there are a lot of works that have been carried out by different researchers [START_REF] Dubois | Gestion des exigences de sûreté de fonctionnement dans une approche IDM[END_REF]- [START_REF] Guillerm | Global safety management method in complex system engineering[END_REF]. The main safety techniques studied in these papers are Failure Modes and Effects Analysis (FMEA) and Fault Tree Analysis (FTA) [START_REF] Guillerm | Global safety management method in complex system engineering[END_REF]. Since the major objective of this paper is the SysML Safety Profile, please refer to our previous paper for a more detailed comparison of these related research works [START_REF] Mhenni | Automatic fault tree generation from SysML system models[END_REF].

III. INTEGRATED SYSTEMS ENGINEERING AND SAFETY ANALYSIS PROCESS

In this section, the integrated process of systems engineering and safety analysis is presented through a set of steps.

• Step 1: Requirements definition and analysis-I n this step, system functionalities as well as its external interfaces are described by a set of requirements.

Several SysML diagrams such as use case diagrams and block definition diagrams for the system context can be used to help in the identification of these requirements. For more detail about requirement definition and analysis please refer to the steps of the black box analysis in [START_REF] Mhenni | A SysML-based methodology for mechatronic systems architectural design[END_REF]. [START_REF]XML Metadata Interchange (XMI) Specification, Object Management Group Std[END_REF] file generated from the SysML model. The generated FMEA contains the data-sheet with the list of the functions and a generic list of failure modes. The safety expert then performs the analysis and completes the FMEA with the relevant data. All these safety information are then incorporated into the SysML model via the safety profile extension that will be explained in section IV. The gap between safety analysis and design modification is shorten, thanks to this integrated model. At the end of this step, safety requirements are derived and added to the set of requirements. The rule is that for each failure mode with hazardous effects, at least one safety requirement is added. Design changes can be done from this early design stage at the functional level to eliminate or reduce identified risks. Risk effects mitigation can be obtained by eliminating or modifying high risk functions, adding new fault tolerance mechanisms like diagnosis and reconfiguration functions, etc. Each time that the functional architecture is modified, the FMEA shall be updated to take into account the new changes. The previous steps iterate until a satisfactory solution is identified.

•
•

Step 4: Logical architecture definition-Once the functional architecture is defined taking into account the results of the safety analysis in step 3, one or more logical architectures are defined by allocating components to functions. A Block Definition Diagram (BDD) describes the components of the system and an Internal Block Diagram (IBD) describes the interactions between the components. The logical architecture defined at this step already takes into account safety aspects since it integrates the results of the functional safety assessment performed in step 3.

• Step 5: Component-level risk assessment-When the structure of the system is defined, the safety analysis results are updated and a component level risk assessment is performed. For this purpose, a component FMEA is generated from the XMI file like in step 3. To ensure consistency with previous safety analysis, the generated FMEA, in addition to the components, contains in front of each component the functions allocated to the component as well as the failure modes identified at the functional level as a reminder. The safety expert then identifies the failure modes at the component level and performs FMEA analysis. If there are identified risks at a non acceptable level, then these risks shall be eliminated or reduced to an acceptable level by performing changes to the design. Once again, these safety data are saved back in the same SysML model.

• Step 6: Fault tree analysis-The final step is the fault tree analysis. Fault trees are used for both qualitative and quantitative analyses. In our approach, fault trees are automatically generated from SysML IBDs describing the system architecture. Information from the previous FMEA analysis is taken into account to create fault tree with specific failure modes. Fault trees can be generated in a graphical form for qualitative analysis purposes like fault propagation studies and critical paths identifications. They can also be generated in an appropriate format for existing fault tree analysis tools.

For more details about fault tree generation please refer to [START_REF] Mhenni | Automatic fault tree generation from SysML system models[END_REF].

IV. SAFETY PROFILE

During the design phase, the designers (systems or domain engineers) may have relevant information concerning safety especially if they are integrating new concepts or innovating technology. In this case, they are recommended to transmit these data to safety experts. And in the opposite direction, it is important for a safety expert to pass on safety analysis results to systems engineers to take into account in the system design. In order to integrate safety information directly into SysML models, we have used the extension mechanism of UML to create a so called Safety Profile. A profile allows adaptation or customization of UML meta-models to a specific platform, domain or method through stereotype and tag definition concepts [4]. The stereotype is the primary extension construct that extends an existing meta-class. A stereotype may have properties that are referred to as tag definitions. In our case, the Safety Profile is built from stereotypes and tag definitions that represent FMEA artifacts such as failure modes, causal factors, system effects, probability, severity, etc. The relationships between this information are modeled by a class diagram given in Fig. 1.

Since in our methodology, in the functional decomposition step (step 2, section III), a system function is represented by an The other information about a failure mode such as rate, severity, causal factors, detection methods, etc can be simply considered as the tag definitions of the Failure Mode stereotype. Fig. 2 gives a partial profile diagram of our Safety Profile. In a more general framework, we model also the redundancy mechanism as well as dysfunctional behavior information such as degraded and failed states, safety requirements with their formal test cases, etc. In the scope of this paper, we only present the FMEA view of the Safety Profile. It is also noted that there is no unique solution for the safety profile. We prefer to use a simple and efficient solution that allows us to represent all needed information while not overloading the XML Metadata Interchange file generated from the SysML model. In this section, a case study is presented to illustrate the proposed method. An example of electromechanical actuator (EMA) is considered. The EMA aims at actuating the ailerons in an aircraft. The use of EMAs in flight control is increasing since they have many advantages [START_REF] Mami | Définition, conception et expérimentation de structures dáctionneurs électromécaniques innovants incluant par conception des fonctionnalités de sûretée td es écurité de fonctionnement[END_REF]:

• Better environmental respect with suppression of hydraulic power and oil leak risks;

• Weight saving on aircraft;

• Maintenance cost reduction;

• Performance increase and speed accuracy due to electric actuators.

In step 1, the requirements of the system are defined. The main functional requirement of the EMA is to "Control the Aileron Incidence". In this step, a black box analysis is performed to identify the requirements by analyzing the context of the system as well as the functional scenarios. For more detail about the different steps of the black box analysis, please refer to [START_REF] Mhenni | A SysML-based methodology for mechatronic systems architectural design[END_REF]. Then, in step 2, the functional architecture of the system is determined based on the functional requirements identified in step 1. An example of functional architecture of the EMA is given in Fig. 3. Thanks to the safety profile, any data about safety available at the design stage can be integrated in the system model. If some functions have specific failure modes, the designers can integrate them in the system model so that the safety expert could take them into account. For instance, Fig. 4 shows a failure mode "Specific failure mode" added in the system model for the function "Translate Pilot Instructions". This is done via the FailureMode stereotype which is an extension of the Parameter meta-class of the activity "Translate Pilot Instructions". This stereotype allows adding some properties to the failure mode in the system model which will be included in the generated FMEA as well. An extract of the generated functional FMEA is given in Fig. 6 including the "Specific failure mode" as well as the corresponding causal factor and system level effect entered in the system model (manually highlighted in red for the readers). Other important information such as potential causes and effects are also pre-filled. An extract of generated datasheet for the EMA is given in Fig. 6. The safety expert then completes the data-sheet, identifies critical functions and tries to eliminate or reduce the effect of potential risks. Additional data completed by safety expert are then saved back to the SysML model via Safety Profile elements.

For this example, several single failures may lead to the system effect "Aileron locked" which may result into a loss of control of the aircraft. This risk shall be reduced by adding a new function "Internal Diagnosis". The system shall be able to detect failures and prevent the catastrophic effects they may have. New iteration of FMEA is performed to take into account the modified design. The added function "Internal Diagnosis" will be integrated in the FMEA and its failure modes and their impact on the system behavior will be analyzed. We consider that this is the only modification of the design and we will then move to the step 4 where the system structure is defined by allocating components to functions. The resulting system structure is given in Fig. 8. In the same way, a component FMEA is generated based on the system structure model (step 5). It contains the list of components, and for each component, the list of allocated functions (activities) to improve the consistency between the functional analysis and the component analysis. If several structural solutions are proposed, then several FMEAs are generated and the different solutions can be compared according to safety analysis. If any changes or improvements can be done to the system structure based on the results of safety analysis, then new iterations are performed to take into account the design changes and assess their impact on system safety. In the same way as for the functional FMEA, the safety profile allows systems engineers or designers to integrate some safety aspects into the system model and these will be automatically integrated into the generated component FMEA. Fig. 9 shows an example of component failure mode added in the system SysML model. The same properties as in Fig. 5 can be added in the system model for each failure mode. The last step is step 6 relative to fault tree analysis. This step is based on the results of the previous design steps and safety analyses. More detail about fault tree generation can be found in [START_REF] Mhenni | Automatic fault tree generation from SysML system models[END_REF].

VI. CONCLUSION

In this paper, we have proposed an implementation of the Safety Profile that extends some UML modeling elements to represent FMEA information namely failure modes, probability, severity, causes and effects. Combining this profile with SysML elements such as activities for functions and blocks for components, we are able to carry out the preliminary safety analysis within the mechatronic system design process by using the integrated methodology.

Automatic generation of FMEA data-sheets and of fault trees from the system structures can be a good support for safety experts. The consistency between the latest design modifications and the safety information is ensured by this SysML Safety Profile. In addition, our integrated framework can help systems engineers to keep traces between safety requirements and different functional and architectural solutions, which is very important for safety-critical mechatronic systems.

The further step of our work is to enrich the Safety Profile to take into account different fault tolerance mechanisms such as redundancy policies, as well as to integrate formal methods to validate system dynamic behaviors with respect to safety requirements. Another extension of the profile concerning some mechatronic issues such as the connection components and the multi-physical interactions among components is also studied.

Fig. 1 .

 1 Fig. 1. Class Diagram for FMEA Artifacts

Fig. 2 .

 2 Fig. 2. Safety Profile Diagram

Fig. 3 .

 3 Fig. 3. Functional Architecture

Fig. 4 .

 4 Fig. 4. Example of Failure Mode Added in the System Model

Fig. 6 .

 6 Fig. 6. Generated Functional FMEA In step 3, and based on the functional decomposition of step 2, an FMEA is generated with the list of the functions in the system model. For each function, generic failure modes are

Fig. 7 .

 7 Fig. 7. Updated Functional Architecture

Fig. 9 .

 9 Fig. 9. Example of Failure Mode Added to a Component in the System Model


Nesrine Ben Yahmed

Hélène Carrère

Issam Smaali

Hélène Carrere

Coupled production of biogas and date-syrup via biorefinery concept using

teaching and research institutions in France or abroad, or from public or private research centers.

Introduction

Date production is usually associated with a considerable loss either in common cultivars such as 'Kenta' or in fruit picking and storage stages. This discarded biomass is not very well valued up to now especially in bioenergy production.

Methodology

•

Biochemical characterization of Kenta flesh, fibers and date syrup.

• Development of a biorefinery concept based on the co-production of date-syrup and biogas.

Objectives

Results

Chemical composition of dates fleshes and extracted dietary fibers (DF) Development of a biorefinery concept based on soluble sugars extraction and biogas production

Conclusion and perspectives

This study presents a proof of a sustainable biorefinery approach allowing a complete bioconversion of undervalued secondary date variety. Optimization of the process steps is necessary. The biochemical composition analysis showed that Kenta fibers contain mainly carbohydrates (33.2 % VS± 0.7%VS) and proteins (8.8% VS ± 0.1% VS) making it a suitable substrate for biogas production.

  .benyahmed@gmail.com / helene.carrere@inrae.fr /Issam.Smaali@insat.rnu.tn Publication: Ben Yahmed et al, New sustainable bioconversion concept of date byproducts (Phoenix dactylifera L.) to biohydrogen, biogas and date-syrup, International Journal of Hydrogen Energy, Vol 46,Pages 297


Mahdi Aicha

Imen Belhadj

Moncef Hammadi

Nizar Aifaoui
email: nizar.aifaoui@ipeim.rnu.tn

A mathematical formulation for processing time computing in disassembly lines and its optimization

Disassembly is the first practice in maintenance and recycling of industrial products. For productivity and efficiency, it is necessary to optimize its operative manners by reducing: change of tools and directions, process variation, wastes, etc. The simulation of Disassembly Plan (DP) allows the detection and identification of difficulties from the design stage in order to avoid them.

This paper proposes a mathematical formulation which combines two principal indicators: the index of Quality (Qi) and the index of processing Time (Ti) in order to choose the best and feasible disassembly plan. The Failure Mode, Effects and Criticality Analysis method is implemented to compute Qi. Ti is obtained according to real manufacturing constraints (workspace, layout, tools, machines, etc.). Based on 5S method, the workspace can be optimized which directly impacts the timing index and contribute to the selection of the best DP. A gear box is used to show up the efficiency of the proposed approach.

Introduction and literature review

Recycling as well as remanufacturing are significant from an economic perspective, protecting environment and conserving resources. In this field, when starting-up a new project, processing time (disassembly preparation and operation) is a main indicator that managers take in consideration to correctly assess the revenue. In all organization, industrial engineering team precisely evaluates disassembly operations and preparations time (manual or machinery operation) aiming to decrease it and avoid wastes in order to accomplish the efficiency goal. This assessment can be efficient if it is obtained using feasible disassembly plans generation (APG/DPG) and considered during the design phase. This paper proposes a mathematical formulation which combines two principal indicators: the index of Quality (Qi) and the index of processing Time (Ti), as criteria whereas choosing best and feasible disassembly plan. The Failure Mode, Effects and Criticality Analysis method (FMECA) is implemented to compute Qi. Ti is obtained according to real manufacturing constraints (workspace, layout, tools, machines, etc.). Based on 5S method, the workspace can be optimized which directly impacts the timing index and contribute to the selection of the best DP. The next section details a review on APG/DPG and its automation.

Review on APG / DPG and its automation

The first researches regarding APG/DPG problems are just theoretical and wholly disconnected to Computer Aided Design (CAD) systems. The integration of APG/DPG approaches in CAD tools begins by the earliest development on informatics technologies. A matrix representation of liaisons by using binary codes is used to generate APG/DPG. The proposed square matrix is manually created, [START_REF] Dini | Flexible and process integrated knowledge bases as instruments for modern CAPP systems[END_REF]. Computer-aided techniques and methods were proposed to extract liaison matrix throughout Application Programming Interfaces (APIs) from CAD tools to perform APG/DPG [START_REF] Gandouzi | A CADDEX tool for CAD and CAE integration[END_REF][START_REF] Aicha | A Coupled Method for Disassembly Plans Evaluation Based on Operating Time and Quality Indexes Computing[END_REF][START_REF] Vigano | Assembly planning with automated retrieval of assembly sequences from CAD model information[END_REF][START_REF] Li | Assembly modeling for 3d component based on polychromatic sets[END_REF]). An AND/OR graph is developed to represent (Assembly Plans) APs. For complex mechanisms, the proposed method which is limited to traduce the AP only as a graph representation becomes complex and difficult to manipulate. For a mechanical product, a subset recognition method is developed using a set of matrices such as: the relationship matrix, the contact matrices and the anteriority matrices according to the three directions of the assembly. With this approach, the planner intervention is needed to generate feasible subsets [START_REF] Dini | Automated sequencing and subassembly detection in assembly planning[END_REF].

For the automobile field, a mathematical model to generate feasible APs is proposed [START_REF] Zang | Automated sequencing and subassembly detection in automobile body assembly planning[END_REF]. Since remanufactured parts should be already dismounted, disassembly is a significant step in the recovery of End of Life machines (EoL). DPG is a crucial step of the disassembly process focused on determining an optimal meticulous disassembly plan for eliminating specific parts or subsets from a mechanism [START_REF] Lambert | Determining optimum disassembly sequences in electronic equipment[END_REF][START_REF] Gungor | Disassembly sequence plan generation using a branch-and-bound algorithm[END_REF]. Moreover, based on the total disassembly process, partial disassembly becomes an increasing focus of attention compared to previous research investigations [START_REF] Rickli | Multi-objective partial disassembly optimization based on sequence feasibility[END_REF][START_REF] Smith | Partial disassembly sequence planning based on cost-benefit analysis[END_REF]. In the same context, based on a standard format which is the STEP format (STandard for the Exchange of Product model data), To produce feasible APs, a new integrated CAD method is developed based on the investigation of relationship matrices. The proposed approach needs the aid of the planner in some needed data [START_REF] Su | Computer aided geometric feasible assembly sequence planning and optimizing[END_REF][START_REF] Mathew | A novel method of using API to generate liaison relationships from an assembly[END_REF]. Design for disassembly (DFD) is a main methodology to create mechanisms easy for maintenance and reuse practices. The choice of connecting parts (screw, pin, rivet, etc.) used in a mechanism is one of the significant questions in DFD. [START_REF] Gungor | Evaluation of connection types in design for disassembly (DFD) using analytic network process[END_REF] proposed a substitute connection elements based the high ability of the Analytic Network Process (ANP). The proposed method produces a whole ANP representation that integrates panoply of propositions for the selection of connector parts. The proposed ANP model assesses alternative connectors based on three major features: create a friendly product disassembly; create an efficient product assembly and rising the performance when the mechanism is exploited. Afterward, researches in robotic disassembly began. [START_REF] Elsayed | A genetic algorithm approach to end-oflife disassembly sequencing for robotic disassembly[END_REF] proposed a methodology which uses a Genetic Algorithm (GA) for DPG of EoL mechanisms in disassembly processes based on robots. However, collaboration between robots and humans remains the main issue. ElSayed, Kongar, Gupta, and Sobh (2011), [START_REF] Elsayed | A robotic-driven disassembly sequence generator for end-of-life electronic products[END_REF] developed a smart automated disassembly unit for online selective disassembly. More recent researches done by [START_REF] Vongbunyong | A framework for using cognitive robotics in disassembly automation overview of cognitive robotics[END_REF][START_REF] Kuo | Waste electronics and electrical equipment disassembly and recycling using Petri net analysis: Considering the economic value and environmental impacts[END_REF][START_REF] Vongbunyong | Learning and revision in cognitive robotics disassembly automation[END_REF] propose other accomplishments in robotic dismounting, mostly in the use of cognitive robotics and vision-based systems. The proposed smart method pays attention on the reduction of the fuzzy and the variation that exist in the dismounting procedure. According to the authors, the proposed approaches eliminate the necessity for human intervention to produce required information. According to [START_REF] Habibi | An efficient two-phase iterative heuristic for collection-disassembly problem[END_REF], concluding the round in the production lines is one of the obligatory constraints for best permanent development. The disassembly planning comes in the reversal level of the production lines. The main objective is to collect the tasks of EoL of machines. The disassembly process is necessary for powerful reuse and recovering of retained parts or subsets. The developed approach is based on iterative two steps using heuristic method to efficiently associate huge size occurrences. The numerical investigations demonstrate that the heuristic aspect gives high-quality results with satisfactory calculation time.

Parallel mounting and dismounting methods based on robot and human cooperation can raise the design quality by selecting the lower solution to wholly dismount the mechanism or to dismount wear parts (bearing, sealing gasket, etc.). The programming of these techniques in CAD systems can improve the today's industry efficiency by several aspects as: decrease product cost, reduce time to market and enhance the product quality. In this context [START_REF] Belhadj | Generation of disassembly plans and quality assessment based on CAD data[END_REF], 2021) proposed an original method to dismount totally a complex mechanism with a parallel process. Collision matrices according to the three directions of the assembly are used to produce feasible Disassembly Plan (DP). Additionally, a set of evaluation indexes (design efficiency, recyclability, disassembly time and dismounting parallelism) are considered to enhance the design quality of the proposed solution. In a preventive maintenance context, a wear part priority criterion is added in an extended method to propose a new feasible and optimal DP. The part and subset's disassembly time considered in the proposed approach is inspired by industrial practices [START_REF] Belhadj | Time computing technique for wear parts dismantling[END_REF]. Wang, Mitrouchev, Li, & Lu, (2014) proposed a virtual environment for the disassembly operations evaluation through the development cycle of products by predicting manufacture, maintenance and EoL. In the assessment procedure, various criteria are considered such as: parts and subsets stability, disassembly orientation, tool and direction change. Based on the stability of components during the assembly operations of heavy machines, [START_REF] Bedeoui | Tool workspace consideration for assembly plan generation[END_REF] proposed an original method to produce feasible Assembly Plans (APs) using relationships between parts and subsets. Furthermore, to increase the value of the generated APs the number of the retained criteria is augmented. An extend approach based on three sub-routines is developed. The first sub-routine creates a list of APs. Based on an assembly tools (ATs) workspace criterion, the second subroutine treats the obtained APs ad retains the valid ones. The third sub-routine is used to minimize the change of ATs through.

The improvement of human and robot contribution in maintenance and product disassembly, that are important in EOL preparation and sustainability is necessary in today's industry. However, most maintenance and disassembly tasks are still carried out manually. Consequently, a concurrent architecture that integrates appropriate human issue and ergonomic environment is proposed by Siew, Chang, Ong & Nee, (2020). In the same context, [START_REF] Ramirez | Economic modelling of robotic disassembly in end-of-life product recovery for remanufacturing[END_REF] developed a new method to implement a disassembly process based on robotic intervention for EoL of mechanisms. Moreover, the proposed algorithm helps the robotic unit to carry out the disassembly operations. Including two collaborative robots and a human worker [START_REF] Huang | An experimental human-robot collaborative disassembly cell[END_REF] proposed a disassembly unit based on collaborative robots. Human and robot can work securely in a common environment to execute disassembly operations which can be sequential or simultaneous.

Review on APG / DPG evaluation techniques

APG/DPG evaluation techniques are commonly used to validate the obtained results. Several modeling tools are used (Petri net, stochastic and probability approaches, etc.). Furthermore, quality tools are introduced to evaluate APG/DPG by anticipating production and workspace conditions at the early design stages. [START_REF] Kuo | Waste electronics and electrical equipment disassembly and recycling using Petri net analysis: Considering the economic value and environmental impacts[END_REF] proposed a disassembly tree based on a Petri net which includes only one non-leaf output. It includes four main steps: identify the disassembly tree; determine the assembly rate, construct and evaluation the final disassembly tree. In this approach the planner intervention still significant, moreover, the feasibility of the generated DP is not guarantee. Tian et al., (2012Tian et al., ( , 2012) ) developed an assessment method for complete disassembly procedure of mechanisms with stochastic approach. According to the authors, the input data are manual and the disassembly operations are sequential.

To produce best and feasible DP, Belhaj, Hammadi, Trigui & Aifaoui, (2020) developed a methodology which evaluates the feature of the generated DPs. the Failure Mode, Effects and Criticality Analysis (FMECA) and Ishikawa method are implemented in the proposed model. This quality assessment has optimized the decision of the DP generation but still exist other enhancement parameters such as the processing time indicator. Later, Lean tools have been slightly introduced in the APG/ DPG. Lean can be referred by many names: lean manufacturing, lean enterprise, lean production and lean office [START_REF] Chiarini | Lean production, Toyota Production System and Kaizen philosophy: A conceptual analysis from the perspective of Zen Buddhism[END_REF].

Literature synthesis and positioning of the main novelties

The above-mentioned literatures can highlight the following points:

• The developed works on APG/DPG are based on mathematical foundations but not fully automated and integrated to CAD systems.

A lot of research works remain to be done.

• For the APG/DPG, numerous parameters are considered as: gravity center, mass of part, execution tool, mounting/dismounting trajectory, precedence constraints, time of disassembly/assembly time, etc.

• Quality assessment of APG/DPG not yet elaborated. Nevertheless, these tools are commonly used in multiple industries. The integration of Quality tools in the APG/DPG can engender indisputable benefits.

• MUDA (motion, transport…) associated to practical process execution, non-ergonomic workplace, bad equipment and non-optimal material distribution are not yet considered to evaluate APG/DPG. The integration of the real operating time, according to industrial practices, in the assessment of APG/DPG can produce optimal ones. This paper develops the mathematical formulation of the practical operating time of DPG of mechatronic systems. The question that arises at this level is: "Why do the authors conduct the research around the operating time computing in production lines?". In fact, the abovementioned literatures introduced theoretical disassembly time which does not include real conditions of the workspace. This paper breaks down disassembly time in depth according to industrial practices. The proposed model should put a focus on waste identification and additional motions that can be caused by bad working area and setting-up. These aspects can induce ergonomic problems, bad equipment's and material dispatching. Based on a real workspace, this approach evaluates the necessary operating time for every DP and generates the optimal one. Consequently, the proposed model can evaluate the list of generated DPs and contribute to the choosing of the optimal one.

The main novelty that this approach shows is focused on the evaluation of the previously generated DPs. This evaluation refers to the coupling of two parameters: Ti and Qi. The Qi is precisely presented in [START_REF] Belhadj | Generation of disassembly plans and quality assessment based on CAD data[END_REF]. On the other side, Ti is defined with reference to the computation of the real disassembly time which is done based on industrial practices and real working environment such as: layout, process setting-up, disassembly tools, pressure machine, etc. Based on the proposed approach, for every disassembly plan two metrics are assigned: Ti and Qi. The disassembly plan that corresponds to the lowest execution time (Ti) and to the highest quality index (Qi) is selected as the best DP in terms of: real operating time, change of directions, use of tools, ergonomics. Additionally, and in order to have visual information which is more representative than numbers, a difference parameter (gap), mathematically represented by Δi, is introduced. The gap parameter represents the difference between Ti and Qi. In target of optimal DP condition satisfactory aiming at minimizing Ti and maximizing Qi, the Δi rate must be at its minimum value.

Proposed approach

The process flow of the main approach in this paper is represented in Fig. 1. The proposed approach follows four phases in sequence:

(1) DPG phase: it defines the generated disassembly plans.

(2) Real disassembly processing time calculation step: It consists on the estimation of the real disassembly time for each DP based on industrial practices. With a lean background, this step aims at evaluating the disassembly processing time by detecting wastes then eliminates them.

(3) Quality evaluation step: it consists on the quality assessment of every disassembly plan with calculation of a quality index called Qi (extracted from FMECA tool). (4) A gap parameter estimation step: It is calculated by the difference between Ti and Qi and characterizes the main parameter in the proposed approach.

In target of highlighting the main steps of the proposed approach and proving the added value, an industrial case study is introduced in the following section.

Industrial case study and associated DPG

The industrial mechanism founded from the literature (Belhadj et al., Fig. 1. Architecture of the proposed approach.

2019) is a 17 parts' gear box. Fig. 2 illustrates its exploded view and its decomposition into six subsets.

The DPG process (its flowchart is represented in Fig. 3) starts with the instant delete of all parts of connection (CPs). This approach is based on two principal steps. First of all, the subsets (a subset is a previously defined as part/group of parts) disassembly plans generation. Secondly, the DPs are regenerated in details by recalling connecting parts which were previously eliminated. The DP procedure begins by uploading the interferences matrices following k axis which can be x, y or z axis [IMsubk]. From [IMsubk] each line or column null allows to initiate a DP by dismounting the corresponding subset (SUB). Once a SUBi is disassembled, the corresponding column and line are deleted from [IMsubk] and a new matrix (size n-1) is generated. This loop process keeps, continuously, running until all SUBs are disassembled. Concerning the treated mechanism, Fig. 2 shows a summary of the 32 feasible disassembly plans generated from the DPG procedure.

Real disassembly processing time calculation of DPG

In industrial organizations, management team puts their main focus on balancing between cost, quality and time while treating business. This way of thinking is particularly extracted from iron triangle, called also project management triangle. In order to evaluate the disassembly processing time, a deep analysis and anticipation of the workplace elements is elaborated, such as: layout, process setting-up, accessibility, Fig. 2. Exploded view and subsets decomposition of the case study. Operations inside production site can be classified into three categories:

• Tasks with essential added value: necessary for product manufacturing.

• Non-added value tasks but necessary: these tasks are inefficient, but cannot be removed.

• MUDA (waste): operations without added value and must be eliminated.

Wastes reduction or totally driving them out (by integration of lean tools) if possible, is one of the main objectives that organization aims to reach. This is in order to ameliorate efficiency and improve quality of output. In order to evaluate the disassembly time of the treated mechanism, it is necessary to define the elementary operational time that composes the process. In this approach, the DP is composed of multiple subsets' or component's disassembly operations. The real operating time of DPi (the treated example has generated 32 DPs) is given by formula (1):

T Real DP(i) = ∑ n j=1 ⌊ T prep(j) + T D-sub(j) ⌋ (1)
where

T Real DP(i) :
The global real time of disassembly plan "i". T prep(j) : The total preparation time of the subset "j". T D-sub(j) : The disassembly time of subset "j". The disassembly time of the subset "j" T D-sub(j) is expressed by equation ( 2):

T D-sub(j) = ∑ p k=1 T D-part(k) (2)
where T D-part(k) : Disassembly time of part "k". p: Amount of parts per Subset.

Table 1 summarizes the disassembly time of each subset for the treated mechanism. It is noticed that these elementary disassembly times are obtained by timing in a gearbox overhaul manufacturing company which is based in Tunisia.

b. Preparation time definition: T prep(j)

It is indisputable that simulating a process (assembly, disassembly, manual, machinery, etc) in the real production site shows some unexpected parameters and difficulties. Based on these anomalies, starts the process improvement and optimization until it becomes stable and efficient. The operator's workspace and its workflow is one of the most critical parameters that can influence tasks execution. It can be in multiple cases the root cause behind the existence of some preparations before exercising principal operations. The layout of the workplace of the treated mechanism disassembly process is shown in Fig. 5. The Ishikawa plan exposed in Fig. 6 is employed to detail the impact of the layout on the disassembly execution. During simulations, and according to the working area layout presented in Fig. 5, machinist is required to do various operations (handling, transportation, motion, etc.) in order to be ready for the effective disassembly tasks. Spaghetti diagram is an efficient tool which allows the visualization of physical and informational flows in a workplace. In order to observe the workflow execution, Fig. 5 shows the Spaghetti diagram for the disassembly plan number 1 (Fig. 4).

Operations (preparations) that precede effective disassembly tasks depend on many parameters such as: selection of right tool, transport, motion, manipulation, etc. the needed preparation operations for the disassembly of the treated gear box are shortlisted in Table 2.

Consequently, the total preparation time of a subset (j) is given by formula (3):

T prep(j) = ∑ m k=1 T e(k) (3)
where T e(k) : The timing of the execution task (k) for the subset (j). m: The number of execution tasks associated to the subset (j).

c. Application of the real processing timing calculation on each DP of the case study

According to the disassembly time of each subset provided by Table 1 and all standard preparations given by Table 2, the real processing time can be calculated according to formula (1). Fig. 7 shows the real processing time calculation process for the DP 1 of the treated case study.

To observe the discrepancy of the real processing time between DPs, an indicator Ti was introduced for T Real DP(i) of each DPi and listed in Table 3. Without dimension, Ti index is defined by formula (4). It is noticed that the coefficient 5 in the formula ( 4) is a scale coefficient allowing the different values of Ti to be in the interval [0,5].

For the treated gear box, Fig. 8 presents the (Ti) of each DP of the 32 generated ones. It is noticed that DP 1 has the lowest T i (T 1 = 4.26) and DP 16 comes in the second position with a T 16 = 4.38. Using the Ti criterion, DP 1 and DP 16 belong to the customer satisfaction zone.

T i = T Real DP(i) × 5 max i:1→32 ( T Real DP(i)
)

(4)

Optimization of disassembly processing time: Reduction of preparation time

In order to reduce the preparation time before the disassembly process, Lean tools have been used to optimize to workplace setting-up. 5S method is used to organize tools and standardize workplace. Spaghetti Diagram and MUDA chasing are used to transform lay-out and reduce wastes. The optimized workplace layout and its spaghetti diagram are represented in Fig. 9. The optimized workspace is elaborated using the KAIZEN card which is a Japanese word. KAIZEN means "change to the better", it represents one of the powerful lean manufacturing tools and refers to continuous improvement in performance cost and quality. For the treated case, the KAIZEN card is represented in Fig. 10.

After optimization of the workplace, preparation time is reduced. The real processing time and the timing index Ti are recalculated for each DP. For the gear box, Fig. 11 represents the evolution of Ti for the 32 DP before and after the optimization of the working area.

Quality index formulation

The quality assessment procedure is based on the generated DPs. The principle of this procedure is to estimate the dismounting complexity of each DP by calculating the index of quality (Qi) for each DPi. The Qi is computed after evaluating the Qik of every Disassembly Operation (DOk) which composes the DPi. Given by formula (5), DOk is a list of connecting parts (CP), a disassembly tool (T) and a disassembly direction (D).

DOk = {CP, T, D} (5)
The produced DPs should be classified using the Qi metric and, for the real execution, the planner can select the best DP which has the highest Qi. To calculate the Qi, the FMECA method is used and executed by a working team. In the following section the FMECA method is briefly detailed.

a. FMECA formulation applied to DPG

The FMECA is a methodology to determine all plausible failure modes of a system, as well as the effects obtained by failures and adequate solutions [START_REF] Belhadj | Generation of disassembly plans and quality assessment based on CAD data[END_REF]. Performed by a working team, the FMECA procedure is based on three parameters. The Gravity (G): represents the complexity level to carry out a DOk; the Frequency (F): traduces the incidence of direction and tool change when accomplishing a DOk compared to a previous disassembly operation; the Detection (D): involves wear components in the DOk and measures the complexity level of its access.

Each parameter G, F and D is associated to a value (the minimum is 1 and the maximum is 4). This interval is proposed by the FMECA working team and can be change depending on the treated case. Formula (6) gives the Criticality Failure Mode value (CFM) of each DOk. The minimum value of CFM which is 1 (1x1x1) corresponds to a good design and reliability of the mechanism. However, the maximum value which is 64 (4x4x4) corresponds to a worst design and reliability of the mechanism. In this case, design modifications are needed.

CFM = G.F.D (6)
b.

Qi computation

To evaluate the quality of a DP, Qi is calculated using formula ( 7), where k is the total number of subsets, Qij is given by the addition of qi as shown in formula (8). The qi values depended on the CFM limits. The working team selects the qi values according to the treated mechanism, using formula (9). The qi values can be change from a system to another. However, qi must be inversely proportional to CFM is the main rule for defining qi values. For the treated case study, Fig. 12 presents the Qi progress of the 32 DPs of the gear box. It is noticed that DP 15 has the highest Qi (Q 15 = 2.9). DP 5 and DP 16 come in the second position with Q 5 = Q 16 = 2.8. Using the Qi criterion, DP 15 , DP 5 and DP 16 belong to the customer satisfaction zone.

Qi = 1 ∑ k j=1 Qij (7) Qij = ∑ 5 i=1 qi (8) ⎡ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎢ ⎣ 1 ≤ CFM ≤ 8→qi = 1 5 8 < CFM ≤ 14→qi = 1 4 14 < CFM ≤ 24→qi = 1 3 24 < CFM ≤ 64→qi = 1 2 ⎤ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎥ ⎦ (9)
Based on the previous study on Ti and Qi indexes, it is noticed that DP 1 and DP 16 belong to the customer satisfaction zone according to the Ti index. However, according to Qi index DP 15 , DP 5 and DP 16 belong to the customer satisfaction zone. In order to choose the best DP according to the two indicators (Qi and Ti), a deep analysis is performed.

Difference (Ti -Qi) gap evolution

After calculation of Ti and Qi indexes, the selection of the best DP solution is now elaborated based on both of them simultaneously. Thus, the optimal disassembly plan should correspond to the highest index of quality (Qi) and lowest index of processing time (Ti) in the same time. Formula (10) gives the condition that allows this duality.

DP optimal = [max(Q i ); min(T i )] (10)
To satisfy the optimal DP condition given by formula (10) and defines the best DP, a gap index (Δ) traduces the disparity between Ti and Qi and given by formula (11). Table 4 shows values of Ti, Qi, and Δi of every disassembly plan for the gear box.

Δi(DP i ) = T i -Q i (11)
At this advanced phase, Ti, Qi and Δi are plotted simultaneously in a composed diagram exposed in Fig. 13. To accomplish constraints of optimal DP that minimizes Ti and maximizes Qi, Δi has to be minimal as shown by formula (12).

{minΔ i (DP i )}⇒{DP best = [max(Q i ); min(T i )]} (12)
From Fig. 13 it can be noticed that the smallest rate of Δi corresponds to Δ 16 , associated to D 16 , which is equal to 1.58. Consequently, DP 16 represents the best DP following to Qi and Ti indicators.

At second level, Δi is recalculated but this time with taking Ti values after the transformation and optimization of the workplace. In order to visualize the difference between Δi before and after the transformation, all the Δi for the 32 treated DP are represented in Fig. 14.

From Fig. 14 it can be concluded that there is multiple transformation in values of Δi. Some of them have increased and some other has decreased. But, the smallest value of Δi still corresponds to Δ16, [START_REF] Belhadj | Time computing technique for wear parts dismantling[END_REF] developed a method to select the best DP based on a quality index. The proposed method was accomplished that the best DP is DP 15 with a Q 15 = 2.90. In the current method, judgment was based on coupled indicators which are Ti and Qi. Based on the new approach, it was concluded that DP 16 having the couple (T 16 = 4.29; Q 16 = 2.80) is chosen as the best one. In fact, based on Qi index, Q 15 = 2.90 is higher than Q 16 = 2.80, consequently DP 15 is the best one. However, based on Ti index, T 15 = 4.53 is higher than T 16 = 4.29, which leads to choose DP 16 as the best one. According to the gap index Δ which combine Qi and Ti a couple formula, Δ 16 = 1.49 is lower than Δ 15 = 1.63. Accordingly, in relationship with the Quality-Time-Cost balancing concept, efficiency and productivity, it was concluded that DP 16 is better than DP 15 . Moreover, for various reasons as delivery date, cost, production capacity, etc. flexibility can be considered to the DP selection procedure. A set of five zones classified, according to Δi. The satisfaction zones can be divided as below:

Discussion and synthesis

• Satisfaction zone which includes D 16 , D 15 , D 1 and D 5 . Fig. 15 shows the satisfaction zones as a set of interconnected spheres. The boundary spheres can be defined by the working group.

Conclusion and future work

This research develops a mathematical formulation for processing time computing in disassembly lines and its optimization. The input of the proposed approach is a set disassembly plans (DPs). The generated DPs are, firstly, classified using a real processing time index (Ti) which is obtained by a depth study of disassembly preparations and operations. A quality index (Qi) is also used to evaluate DPs according to an FMECA methodology. A coupling model between Ti and Qi given by a gap index Δ is then developed in answer to the Quality-Time-Cost efficiency and productivity concepts. Using Δ the best DP having the lowest Ti and the highest Qi which correspond to the lowest Δ is chosen. In order to optimize the results a 5S method in proposed in order to reorganize the workspace for reducing the spaghetti diagram of DPs. The best DP which has the minimal Δ and the optimal workspace can be selected. The major advantages of the proposed approach are:

• The use of a mathematical formulation to generate a real processing time model and a timing index. The selected DP must have the lowest value of Ti.

• The use of the FMECA method to select the best DP having minimum direction and tool change in the disassembly operation and facility access of wear parts.

• The classification of DPs using a gap index Δ which combine the two indexes Qi and Ti.

• Lean tools and industrial practices are considered to develop the proposed model.

The proposed approach can be enhanced by taking into account further aspects. As a future work, the cost and the consumed energy criteria for disassembly preparations and operations can be integrated. Furthermore, formula (11) which calculates the gap Δi uses the same weight of Ti and Qi. A parametric study on the weights of Ti and Qi can be elaborated in order to study the Δi evolution.

Fig. 3 .

 3 Fig. 3. Architecture of the DPG process.

n

  : Number of Subsets in the assembly. a. Disassembly time of subset : T D-sub(j)

Fig. 4 .

 4 Fig. 4. List of DPs of the case study.

Fig. 5 .

 5 Fig. 5. Workplace with the associated Spaghetti diagram applied to DP 1 of the case study.

Fig. 6 .

 6 Fig. 6. Ishikawa diagram.

Fig. 7 .

 7 Fig. 7. Real processing time calculation for DP 1 of treated case study.

Fig. 8 .

 8 Fig. 8. Timing index evolution for the 32 for the treated case study.

Fig. 9 .

 9 Fig. 9. Optimized workplace and the new Spaghetti diagram of DP 1 of the treated mechanism.

Fig. 10 .

 10 Fig. 10. Optimization of the workspace based on the KAIZEN card.

Fig. 11 .

 11 Fig. 11. Ti evolution before and after the optimization.

•

  Moderately satisfaction zone which includes D 6 , D 2 , D 24 , D 7 , D 3 . • Minor modification needed to reach the satisfaction zone which includes D 17 , D 23 , D 11 , D 4 , D 13 , D 14 . • Major modification needed to reach the satisfaction zone which includes D 18 , D10, D 29 , D 31 , D 32 , D 8 . • Rejection of DP for inability to reach the satisfaction zone which includes D 12 , D 19 , D 30 , D 21 , D 9 , D 22 , D 28 , D 20 , D 26 , D 25 , D 27 .

Fig. 12 .

 12 Fig. 12. Evolution of the Qi for the 32 DPs for the case study.

Fig. 13 .

 13 Fig. 13. Qi, Ti and Δ indexes for the 32 DPs for the case study.

Fig. 14 .

 14 Fig. 14. Δi evolution before and after the optimization.

Table 1

 1 Detailed disassembly time of each subset.

		Dismounting and removing operation	Tool (M: manual; Pm: Press-machine; Er: Elastic-ring Screwdriver tool; Sd:	Elementary dismounting time (s)	Total dismounting time (s)
	Sub1 Sub2 Sub3 Sub4 Sub5 Sub6	(7) (6) (10) (15) (16) (17) (2) (3) (4) (5) (9) (18) (19) (21) (22) (23) (1) (8) (18) (19) (20) (21) (22) (23) (13) (12) (11) (14)	M Pm Pm M Er Pm M Pm Er M Pm Sd Sd Sd Sd Sd Sd M M Sd Sd Sd Sd Sd Sd M M Pm Pm	15 45 45 35 15 45 15 45 15 35 45 16.5 16.5 16.5 16.5 16.5 16.5 10 20 0 0 0 0 0 0 10 15 45 45	0 0 0 0 0 0 10 16.5 16.5 16.5 16.5 16.5 16.5 10	200 155 (3)→ (5) 109 20 (5)→ (3) 109 105	(5)→ (3) 10 (3)→ (5) 10

Table 2

 2 Standard operations and preparation types.

Table 3

 3 DPs timing index for the gear box.

	DP i	T Real DP(i)	Ti	DP i	T Real DP(i)	Ti
	DP 1 DP 2 DP 3 DP 4 DP 5 DP 6 DP 7 DP 8 DP 9 DP 10 DP 11 DP 12 DP 13 DP 14 DP 15 DP 16	786 823 835 812 842 838 849 845 849 849 865 902 834 861 849 809	4.26 4.46 4.52 4.40 4.56 4.54 4.60 4.58 4.60 4.60 4.69 4.89 4.52 4.66 4.60 4.38	DP 17 DP 18 DP 19 DP 20 DP 21 DP 22 DP 23 DP 24 DP 25 DP 26 DP 27 DP 28 DP 29 DP 30 DP 31 DP 32	849 845 917 890 869 890 905 875 890 863 923 893 852 878 860 826	4.60 4.58 4.97 4.82 4.71 4.82 4.90 4.74 4.82 4.67 5.00 4.84 4.62 4.76 4.66 4.47

Table 4 Δ

 4 computation for the gear box.

	DP i	Qi	Ti	Gap Δ	DP i	Qi	Ti	Gap Δ
	DP 1 DP 2 DP 3 DP 4 DP 5 DP 6 DP 7 DP 8 DP 9 DP 10 DP 11 DP 12 DP 13 DP 14 DP 15 DP 16	2.50 2.60 2.40 2.00 2.80 2.70 2.50 1.80 1.60 1.90 2.30 2.10 2.10 2.2 2.9 2.8	4.26 4.46 4.52 4.40 4.56 4.54 4.60 4.58 4.60 4.60 4.69 4.89 4.52 4.66 4.60 4.38	1.76 1.86 2.12 2.40 1.76 1.84 2.10 2.78 3.00 2.70 2.39 2.79 2.42 2.46 1.70 1.58	DP 17 DP 18 DP 19 DP 20 DP 21 DP 22 DP 23 DP 24 DP 25 DP 26 DP 27 DP 28 DP 29 DP 30 DP 31 DP 32	2.4 2 2.25 1.7 1.8 1.8 2.6 2.7 1.5 1.4 1.6 1.65 1.9 1.9 1.9 1.7	4.60 4.58 4.97 4.82 4.71 4.82 4.90 4.74 4.82 4.67 5.00 4.84 4.62 4.76 4.66 4.47	2.20 2.58 2.72 3.12 2.91 3.02 2.30 2.04 3.32 3.27 3.40 3.19 2.72 2.86 2.76 2.77

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical Approval

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors Contributions

In this paper, a mathematical formulation for operating time computing in disassembly lines and its optimization is proposed.

CRediT authorship contribution statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


domain: chim sdv

text:
Patrick M Dansette

Sulfenic acid as reactive intermediate during thienopyridines activation : Comparison of sulfenic acid trapping methods. Chemical method of formation

Introduction: Thienopyridine antiaggregants are activated into a thiol metabolite that inhibits the ADP platelet receptor P2Y12. This activation proceeds through an 2-oxo-thienopyridine (a thiolactone) further oxidized by cytochrome P45O, into an unstable thiolactone sulfoxide reactive intermediate, that hydrolyses to a sulfenic acid further reduced by reductase or excess reductant (GSH, thiols, DTT, Ascorbate, Phosphines (TCEP) or Arseniate) into the active thiol (1,2).

In presence of a sulfenic trapping agent like dimedone one can isolate an adduct. In presence of reducing agents, formation of thiol competes with the trapping reaction.

The aim of this study is to compare newly introduced sulfenic acid trapping agents (3) and to show the formation of the sulfenic acid by chemical oxidants.

Oxene Donors : 2-oxo-ticlopidine (100 µM) was incubated in presence of microsomes with 1mM dimedone and oxene donors. The dimedone adduct was formed for tBu-OOH (0.5, 1 and 2 mM; yield 6%, 10% and 15% respectively), for Cu-OOH (0.5 and 1mM; yield 22% and 17%). PhIO and incubation in absence of microsomes gave no adduct. Chemical oxidation : 2-oxo-ticlopidine (100 µM) and dimedone 1mM in pH7.4 buffer plus 20% EtOH and NaIO4 (2 mM) for 30 min gave a low yield of dimedone adduct. Oxidation of 2-oxo-ticlopidine in CH 2 Cl 2 with mCPBA and dilution with 1mM dimedone in buffer gave small amounts of the adduct. Further oxidation methods should be tested.

Electrophilic probes :

Strained Alkenes: N-ethylmaleimide (NEM) and N-methylmaleimide were tested at 0.1-2mM. Two Sulfoxide adducts of NEM were found at m/z = 491 (in presence of 18 O 2 only 5% 18 O incorporation) and another product at 473 (37% 18 O) that could be the Diels Alder (DA) adduct of the hydroxy-thiophene sulfoxide (OH-TSO) or of a conjugated thione? (6). N-Methylmaleimide gave similar results. These adducts decreased at the same rate with nucleophilic competitors (GSH or dimedone or indanedione) thus derive probably from the same intermediate.

The norbornene carboxylic acid, carboxamide and diacid were tested (1-8 mM). The acid gave the best results, with the expected sulfoxide adduct at m/z = 504 plus another at 486 : (the OH-TSO DA adduct ?)

Strained alkyne: Only BCN was tested. It gave two adducts at m/z = 498 (possibly the OH-TSO DA adduct) and a broad peak at 514 (dehydrogenated from the expected SO adduct 516 (unknown)).

References: 1) Dansette PM, Libraire J, Bertho G, Mansuy D. Metabolic oxidative cleavage of thioesters: evidence for the formation of sulfenic acid intermediates in the bioactivation of the antithrombotic prodrugs ticlopidine and clopidogrel. Chem Res Toxicol. 2009; 22(2):369-373. 2 Methods : incubations of 2-oxo-prasugrel (100 µM) in presence of rat or human liver microsomes (1mg/mL) NADPH (1 mM) were done accordingly to reference 2. In absence of NADPH, oxene donors were tested (tBuOOH, CuOOH) in absence or presence of microsomes. For chemical oxidation 2-oxo-thienopyridines were reacted with diverse oxidants in presence of dimedone. The trapping agent were nucleophiles: thiols, cyanide, thiocyanate, dimedone, cyclopentane-1,3dione, and analogs or strained alkene or alkyne (ethyl-maleimide, norbornenes and BCN). Several concentrations (0.1-20mM) were tested and competition with 1 mM dimedone were also done. After 30 min incubation the reaction was stopped with half a volume of AcCN/AcOH 9/1 and centrifuged. The supernatant was analysed by HPLC/MS and MS 2 using a Thermo LCQ Advantage or an HRMS Exactive Orbitrap (2).

Results : New sulfenic acid probes have been described (Scheme 2, (3-5)). All were tested with oxo-prasugrel and oxo-clopidogrel. Nucleophilic probes: Thus prasugrel or 2-oxo-prasugrel metabolised by liver microsomes in presence of dimedone and NADPH gave the expected adduct (2). Experiments with KCN and K 13 CN (0.2-20 mM) gave the expected thiocyanates (SCN) at m/z = 375 and 376 respectively and small amount of an endo isomer. The spectra, MS and MS 2 of the major adduct and its endo isomer are shown (below). Cyanide in competition with 1 mM dimedone decreased the dimedone adduct 50% at 12 mM.

Similarly thiocyanate gave the Sulfo-thiocyanate adduct. (S-SCN : m/z = 407, not shown).

  ) Dansette PM, Thébault S, Bertho G, Mansuy D. Formation and fate of a sulfenic acid intermediate in the metabolic activation of the antitrombotic prodrug Prasugrel Chem Res Toxicol. 2010; 23(7):1268-1274. 3) Gupta V, Paritala H, Carroll KS. Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic probes. Bioconjug Chem. 2016; 27(5):1411-1418. 4) Alcock L.J., Oliveira B.L., Deery M.J., Pukala T.L., Perkins M.V., Bernardes G.J.L., Chalker J.M. Norbornene Probes for the Detection of Cysteine Sulfenic Acid in Cells. ACS Chem Biol. 2019; 14(4):594-598. 5) Kumar M.R., Farmer P.J. Trapping Reactions of the Sulfenyl and Sulfinyl Tautomers of Sulfenic Aciids. ACS Chem Biol. 2017; 12(2):474-478. 6) Karakasa T. and Motoki S. Chemistry of α,β-Unsaturated Thione Dimers 2. Reactions of Thiochalcones and 2-Arylidene-1-thiotetralones with Some Olefins and the Parent Ketones of the Thiones. J Org Chem. 1979; 44. 23:4151-53.

5

  -Methyl-cyclohexane-1,3-dione gave two adducts (diastereo-isomers) (m/z = 474) at level similar than dimedone (m/z = 488), cyclopentene-1,3-dione gave low level of adducts (m/z = 444, not shown) and Indane-1,3-dione gave two adduct at m/z= 494 and was twice as efficient as dimedone. Piperidine-2,4-dione, two adducts at m/z = 461, was 20 time less efficient than dimedone.

  Scheme 1 : Metabolic bioactivation of thienopyridines N


text:
Patrick M Dansette

Daniel Mansuy

Mechanism of activation of clopidogrel into its active thiol metabolite: P450-catalyzed opening of the 2-oxo-clopidogrel thiolactone : S-oxidation or Baeyer-Villiger oxidation?

Introduction: Clopidogrel and ticlopidine are activated to the thiol active metabolite, that inhibits receptor P2Y12, in two oxidative steps and a reduction: First P450 catalysed oxidation into thiolactones : 2-oxoclopidogrel and 2-oxo-ticlopidine. Second, P450-catalyzed opening into a sulfenic acid (1). We proposed that the thiolactone is oxidized to a thiolactone S-oxide (Path A) that hydrolyzes to a sulfenic acid, reacting with glutathione to give a mixed disulfide, further reduced (enzymatically or chemically) to the active thiol. Alternatively in presence of dimedone the sulfenic acid is trapped as a stable dimedone adduct (1, 2) or in presence of thiols into mixed disulfides that are reduced by excess thiol into the active thiol and its isomers (1). In presence of ascorbic acid, TCEP or DTT, the sulfenic acid is reduced into the active thiol (2).

A Analogous reactive intermediates, a thiolactone Sulfoxide or a 3oxo-1,2-oxathiolane (a carboxylic-sulfenic anhydride), were proposed by Latham and Walsh in the inactivation by thiolactones of a Baeyer-Villiger flavo-protein : cyclohexanone mono-oxygenase (6). allow to verify the incubation conditions (if 18 O water or dioxygen were present in the incubation).

However the dimedone adduct derived from clopidogrel incorporated only one O from dioxygen in the CO of the COOH coming from its thiolactone precursor and only traces of a second oxygen. The OH of the COOH came from water.

Thus the above results agree with Path A or B'. The fact that OH of the carboxylic acid comes from water is not compatible with path B nor C.

However Path B and C is not totally excluded because of the slight incorporation of a second oxygen into the dimedone adduct (3-8%).

Similar results were obtained for 2-oxo-ticlopidine: The 7a-OH of 7ahydroxy-2-oxo-ticlopidine came from 18 O dioxygen. The carboxyle-OH of the dimedone adduct came from 18 O water and not from dioxygen.

Also 2-oxo-prasugrel gave similar results (4).

References:

1) Dansette P.M., Libraire J., Bertho G. and Mansuy D.. Metabolic oxidative cleavage of thioesters: evidence for the formation of sulfenic acid intermediates in the bioactivation of the antithrombotic prodrugs ticlopidine and clopidogrel Chem. Res. Toxicol. ( 2009

  recent paper by Zhu (3) challenges our hypothesis and propose an alternative Baeyer-Villiger oxidation of the thiolactone (Path B) through a 3-oxo-1,2-oxathiolane, followed by nuceophilic attack by the heme-Fe-O -(Path C) to afford the same sulfenic acid intermediate. The aim of our study is to use as end product the sulfenic acid dimedone adduct to analyze incorporation of 18 O from 18 O water or 18 O dioxygen, and compare it to the incorporation of 18 O in other cometabolites in incubations of clopidogrel (and 2-oxo-clopidogrel and 2-oxo-ticlopidine) with rat liver microsomes (RLM), to try to decide between these two hypothical pathways. The 18 O incorporation should be different for each pathway as shown in Scheme 1. Thus starting from clopidogrel the carbonyle (CO) of the thiolactone (2-oxoclopidogrel) and that of the dimedone adduct comes from dioxygen. The OH of the carboxylic (COOH) group comes from water in Path A and B', from dioxygen Path B. In the hypothesis of Zhu (Path C) both the acid OH and the sulfenic OH come from dioxygen. The acid group OH comes from water in Path A and B'. It comes from dioxygen in Path B. In path C the Sulfenic OH comes from spectra of clopidogrel metabolites from incubations with RLM in presence of air or air and 18 O water or 18 O dioxygen and NADPH. Discussion : The results obtained show that only Path A or B' are compatible with the oxygen incorporation found. The slight 18 O incorporation from dioxygen into the dimedone adducts (< 8%) could be due to some exchange or to Path C proposed by Pr Zhu. Thus a Baeyer-Villiger oxidation cannot be fully excluded. Path A and B' (nucleophilic attack at CO) is also compatible with the fact that the reactive intermediate acts as a bis-electrophile (5). Path B and C are not! Diels-Alder adducts with dienophiles of 2-hydroxy-thiophene S-oxides, tautomer of the thiolactone sulfoxides, support Path A ( 7).

Results:

  Scheme 2 : Other microsomal metabolites of clopidogrel