Control Strategy as the Keystone of the Product Lifecycle, from Product/ Process Understanding to Continuous Process Verication and Improvement

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1 Online Exclusive from PHARMACEUTICAL ENGINEERING The Ofcial Magazine of ISPE January/February 2012, Vol. 32 No. 1 Copyright ISPE 2012 This article presents the general principles of Control Strategy (CS) and its evolution. A method for designing a CS and its ling in Common Technical Document (CTD) format are proposed. CS within the continuous process verication and product lifecycle is discussed. Figure 1. The Quality by Design concepts (adapted from Moheb M. Nasr, CDER/FDA, 2010). Control Strategy Control Strategy as the Keystone of the Product Lifecycle, from Product/ Process Understanding to Continuous Process Verication and Improvement by Johanne Piriou, Bernard Elissondo, Michel Hertschuh, and Roland Ollivier Introduction According to the ICH Q10 guideline, Control Strategy is a planned set of controls, derived from current product and process understanding that assures process performance and product quality. Control Strategy includes different types of control proposed by the applicant to assure product quality, such as in-process testing and end product testing. It ensures that the manufactured product has the quality attributes that impact the safety, efficacy, and quality of the product used for the patient. 1,2,3 The Control Strategy has always been a requirement, but this concept has evolved with the implementation of ICH guidelines. 4,5 In a traditional approach to manufacturing process development, Control Strategy describes a set of controls, ensuring, as a whole, the product quality and the control of the sources of variability. In an enhanced approach to manufacturing process development using Quality by Design (QbD) concepts as seen in Figure 1, Control Strategy is based on a better understanding of the product and the process allowing to identify which material attributes and process parameters should be controlled. Scientifically sound and based on risk assessment, this approach allows Control Strategy to focus on components having an effect on product Critical Quality Attributes (CQAs). A CQA is defined as a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. 4 Traditional and enhanced approaches to manufacturing process development are not mutually exclusive. For existing products, without a manufacturing process developed in a QbD approach, Control Strategy can be designed on a combination of both knowledge sources, traditional or enhanced, for control of CQAs, steps, or unit operations. This article deals with the benefits of the implementation of a Control Strategy based on an enhanced approach of the manufacturing process development that generates a better product and process understanding. It shows how the QbD approach can provide pertinent data to design an JANUARY/FEBRUARY 2012 PHARMACEUTICAL ENGINEERING Online Exclusive 1

2 efficient Control Strategy allowing more flexibility to submit it in the regulatory file in CTD format. Finally, it discusses how the Control Strategy plays a central role in the product lifecycle by acting as a major component of continual improvement. Figure 2. An example of Control Strategy in a traditional approach of development. Key Concepts of Control Strategy The demonstration that a manufacturing process ensures that the final product meets its quality criteria has always been a requirement. Nevertheless, with the higher complexity of new pharmaceutical products and processes, an improvement of the Control Strategy became necessary to explain and justify how the product quality is managed. To meet this goal, a detailed description of each mode of control used for each CQA must be provided. In addition, an overview of Control Strategy should provide an understanding of how all these ways of control collectively ensure the product quality. ICH guidelines Q8, 4 Q9, 8 Q10, 9 and Q11 5 and the reflections around their concrete implementation 10,11 reinforced the need for improvement in Control Strategy. The parent guideline on Pharmaceutical Development ICH Q8(R2) 4 introduced the concept of Control Strategy and its link with the control of product critical attributes. This guideline explains that the process control strategies that provide process adjustment capabilities to ensure control of all critical attributes should be described. The ICH Q10 9 guideline published in 2008 goes further in the principles of this concept, defining the Control Strategy as a planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. ICH Q10 integrates Control Strategy as part of the process performance and product quality monitoring system throughout the product lifecycle. Designing and defining an efficient Control Strategy was made possible in 2009 with the publication of the ICH Q8(R2), 4 describing the concepts of Quality by Design, consistent with the new FDA vision. The Control Strategy can indeed be designed on the outputs of QbD approach to product development. For the first time, this guideline establishes a well-developed Control Strategy based on product knowledge and process understanding in combination with quality risk management. 9 The guide Q8(R2) focuses on the identification of the sources of variability that can impact downstream process steps, in-process materials, and finally drug product quality. The key concept for designing an appropriate Control Strategy is to identify and understand the linkage between material attributes and process parameters to product CQAs. This guide highlights an opportunity to shift controls upstream and to minimize the need for end product testing. The ICH Q11 5 guide, published for consultation (step 3) extends application of Quality by Design concepts to the drug substance. It clarifies the possibility for regulatory flexibility, and gives a central role to the Control Strategy. Overall, Control Strategy appears as a keystone allowing: process acquired during development variability of the product and the process is managed process performance throughout the lifecycle Furthermore, ICH Q11 focuses on the existence of two approaches to pharmaceutical development: the traditional one and the enhanced one. The guide underlines that the combination of the two approaches is possible. Benets of Control Strategy in a QbD Approach Every drug substance and drug product, whether developed through a traditional or an enhanced approach, has an associated Control Strategy; therefore, Control Strategy is designed and justified through a traditional or an enhanced approach or a combination of both. Utilizing the traditional way for some CQAs, steps, or unit operations, and a betterdeveloped approach for others, for which the knowledge and understanding are wider, is allowed. As shown in Figure 2, in the traditional approach to Control Strategy, drug product quality is generally controlled primarily by input materials (source and auxiliary), intermediates (inprocess materials), and end product testing. Control of process is realized through in-process controls. Process reproducibility is demonstrated by process validation and change control ensures the maintenance of the product and process state of control. This conventional approach can be considered as a minimal approach. It presents the following issues, detailed below, mainly based on the lack of product/process linkage understanding. First, if the Control Strategy is mainly based on product testing (end product and materials), it is necessary to demonstrate that the analytical methods are appropriate, justifying their reliability and relevance. Indeed, if the analytical testing is not appropriate for the demonstration of a CQA control (i.e., the CQA remains within its specifications), additional control must be considered. Therefore, input and in-process materials testing are usually added, as well as process con- 2 PHARMACEUTICAL ENGINEERING Online Exclusive JANUARY/FEBRUARY 2012

3 trol through in-process controls. But with a reduced product/ process knowledge and understanding, the linkage between input materials control, in-process controls, and final product quality is quite empirical. How do you ensure that a control performed at a certain step of the process ensures the final CQA range? How do you bring the scientific evidence that other process steps do not impact the product when knowledge is tight? Control Strategy based on the traditional approach usually includes demonstration of process reproducibility through process validation for which it is difficult to propose scientific targets and criteria with a limited product/process characterization. Finally, the change control process is used to ensure that the product and process are kept in a state of control. But how do you scientifically demonstrate the non impact of the change with limited knowledge? The traditional Control Strategy approach provides limited flexibility to address variability (for example, raw materials variability), set points, and operating ranges are set narrowly to ensure consistency of the manufacturing process and product quality. 5 These issues and questions are addressed by the enhanced development approach, using Quality by Design. QbD provides the keys to design an appropriate Control Strategy based on better product and process understanding and on identification of the sources of variability in a more systematic way. Drug product quality is ensured by risk-based Control Strategy enabled by well understood linkages between input material attributes and process parameters to output material attributes. Figure 3 shows one example of what a Control Strategy can include in the enhanced approach. This knowledge can provide flexibility in the operating ranges for process parameters to address variability. Thus, quality controls can be shifted upstream with the possibility of real-time release testing, reduced end product testing, or any combination thereof. Figure 3. An example of a Control Strategy in an enhanced approach of development (QbD). Design of Control Strategy in the Enhanced (QbD) Approach In accordance with the QbD concepts expressed in ICH Q8(R2) 4 and ICH Q11 5, the Control Strategy approach is becoming explicit. The first principle is to understand that a Control Strategy, in the enhanced approach, is an iterative process, reviewed as the level of understanding increases during the product lifecycle. Figure 3 shows a schematic view of Control Strategy elements in the enhanced approach. In the design of Control Strategy, the first step is the product description and characterization to identify the product quality attributes that answer to the Quality Target Product Profile (QTPP). (If we take an example of protein purification process, the protein safety is ensured in particular by the CQA content of impurity X. This example is developed in italis, at each step of the approach described in this section.) From the quality attributes, the identification and assessment of the critical quality attributes is performed using risk-based tools. In front of the complexity of pharmaceutical products, the classification and prioritization of the CQAs becomes necessary, by assessment of the quality risk on product safety and efficacy. Not only necessary for product/ process development to prioritize the development studies to increase product knowledge, this prioritization is also needed for Control Strategy justification. Indeed, a CQA that presents a high level of risk on patient safety (e.g., sterility for parenteral products) and product efficacy (e.g., protein activity) should be tightly controlled, and might require multiple control points. Furthermore, the ability of individual controls to detect a potential problem with relevance and reliability must be demonstrated. This can be difficult to assess for functional or characterization assays that can be part of the Control Strategy, but should be confirmed by subsequent control points. The additional control points require process description and characterization to determine the links between product CQAs, process parameters, and material attributes. It is essential, for each process step, to identify the input materials attributes (source and auxiliary materials), the output materials attributes (also called in-process materials), and the process parameters. Then, it is necessary to characterize if these attributes and parameters, at this step, can impact the end product quality. The process parameters and in-process material attributes are classified and ranked as critical for product quality or key for processability as seen in Table A, using quality risk assessment. See below (in italics) an example of a Control Strategy element: it concerns a protein purification process with two purification steps, one Ionic Exchange Chromatography (IEC) and one filtration step. Only the IEC impacts the CQA content of impurity X. Content of impurity X in Intermediate n 1 (input material of IEC step) and in Intermediate n 2 (output of IEC step) are critical in-process materials. IEC medium is auxiliary material attribute that impacts the CQA. The material attributes impacting the CQAs, which control takes part in the Control Strategy, are listed in Table A.The process parameters of IEC, listed in Table B, are 1. linear flow rate, JANUARY/FEBRUARY 2012 PHARMACEUTICAL ENGINEERING Online Exclusive 3

4 CQA Process Step Material ID Unit Operation MATs (IEC) Initial Risk Level Content of Impurity X IEC Intermediate No. 1 1 Impurity X content 2.0% Medium Intermediate No. 2 2 Impurity X content 0.2% High IEC Medium 3 Medium characteristics Medium Table A. Material Attributes (MAs). 2. protein load volume/column volume ration, 3. column bed height. Linear flow rate presents high level of risk for this CQA. The risk assessment of each input material, with regard to the process step where it is used, is essential to evaluate if its quality must be tightly controlled or if there are downstream process steps that can address the material variability. It is built on quality impacts (patient risk) on one side, and processability (manufacturability) impacts on the other side. It is the same method for the in-process materials, in order to determine if at one process step, the attributes must be controlled or not. If the in-process material attribute is important for processability only, the accurate control point that ensures the CQA range has to be implemented later in the process, at a step where it becomes critical to obtain the final target. After this quality risk assessment, for each Critical Process Parameter (CPP), critical input material attribute, critical in-process material attribute identified, a Control Strategy is proposed in order to ensure that the associated CQA is kept within the defined limits. A CPP can be controlled by in-process controls, Process Analytical Technology (PAT), or by operating conditions that are themselves controlled by system (equipment) parameters under monitoring or metrology and maintenance plans. The critical input and in-process material attributes can be controlled by analytical testing such as assays, tests, characterization tests (identity, purity, stability). It is the set of in-process materials control and process parameters control that ensure, as a whole, the CQAs. To summarize, a CQA can be ensured by the combination of several controls: - End product release testing (content of impurity X) - End product characterization (i.e., molecular profiles, amino acid sequences, biochemical assays, physicochemical composition, conformation, purity. Characterization tests are usually used for product comparability demonstration after change) ID Unit Operation CPP (IEC) CQA Impacted Initial Risk Level 1 Linear ow rate Content of 2 Protein load volume/ impurity X column volume ratio High Low 3 Column bed height Low The process parameters of IEC are (1) Linear ow rate, (2) Protein load volume/column volume ratio, (3) Column bed height. (1) Linear ow rate presents high level of risk for this CQA. Table B. Process parameters. - Input material testing for specifications and/or characterization (content of impurity X in intermediate n 1, before IEC step; IEC medium specified and checked) - Manufacturing process operation control (implicit in the design of the process, respect of the operations and their order) - In-process controls including: > process parameters monitoring 1. linear flow rate monitoring continuously during the process; 2. check of parameters, and 3. once per batch > in-process material testing (content of impurity X in intermediate n 2, after IEC step) > Critical System Parameters (CSP parameters directly linked to the equipment technology, process scale, and operating mode) control, including monitoring, trends, records of operating conditions ensuring the CPPs (pressure, temperature continuous monitoring, column efficiency verification after each batch) > Maintenance, calibration to ensure the reliability of the data recorded (pressure and temperature measurements systems verification each month) All the controls identified during the quality risk assessment must be gathered for each CQA to be controlled. This set of controls, classified as product control, material control, process or systems control constitutes the Control Strategy as soon as they take part of a CQA control, whatever it is directly or indirectly. Rationales of Control Strategy must be provided: the methods, frequency, acceptance criteria of each control must be scientifically justified. Example of Control Strategy elements for IEC process is given in Table C. If the approach is driven to a step forward, the variability could be totally controlled by the process and the end product testing could disappear or be minimized, shifting controls upstream, in-line or at-line, thanks to design space(s), to real-time release testing, and to in-process controls (including in-process tests and process parameters). Any alternative approach to the end product testing, shifting controls upstream, must provide at least the same level of product quality assurance, and ensure that no downstream factor can impact the CQA. To conclude, to allow this indirect control of a CQA, minimizing the need for end product testing, an enhanced product and process knowledge and understanding of the sources of variability and their impact on downstream process steps, intermediates and final product is required, combined with quality risk management. An example of links between product and process knowledge and understanding and 4 PHARMACEUTICAL ENGINEERING Online Exclusive JANUARY/FEBRUARY 2012

5 CQA Process Step Material Initial Risk Level Unit Operation MATs (IEC) Residual Risk Content of Impurity X IEC Intermediate No. 1 Medium Impurity X content 2.0% Low Table C. Content of impurity X CS elements. Intermediate No. 2 High Impurity X content 0.2% Medium IEC Medium Medium Medium attributes to be speci!ed and checked Linear Flow Rate High Continuous monitoring of linear "ow rate Pressure and Temperature continuous monitoring Column ef!ciency veri!cation after each batch Maintenance, Calibration on measurement systems Protein load volume/ column volume ratio Low Low Low Check of parameter once per batch Low Column bed height Low Check of parameter once per batch Low Control Strategy elements in a Quality by Design approach are described in Figure 4. The Control Strategy is generally established during product and process development, initially implemented for production of clinical trial batches to insert its description for initial submission of the regulatory file. Enhancement of product and process knowledge at each step of the lifecycle of the product needs continual improvement of the Control Strategy to guarantee the attempted quality of the product. Submission of Control Strategy After establishing the Control Strategy, a detailed description of all the means and individual elements to control each CQA must be presented in the submission file, in accordance with the regional regulatory requirements. Control Strategy and its justification are one of the minimum elements to present in the Chemistry Manufacturing and Controls (CMC) part of the file for its evaluation by the FDA authorities. 12 Regarding the file in CTD format (ICH M4Q 13 ), the localization of data concerning the Control Strategy are so far not-well established. As proposed by ICH Q11, the data should be separated in different sections. This breakdown of the Control Strategy elements can be understood by the previous explanation of the Control Strategy design: CQA control can be a combination of elements derived from product control and others linked to in-process controls, addressed in various sections of the file in CTD format. The overview of the overall Control Strategy of the Drug Substance (DS) can be provided in 3.2.S.4.5 (3.2.P.5.6 for drug product), an analytical section devoted to justifying the specifications (release criteria). The enhanced Control Strategy enables scientific justifications in this section for the methods frequency and acceptance criteria. In addition, the detailed information about the individual elements of the Control Strategy should be described in the devoted CTD section. Figure 5 shows an example of the links between the different CS elements and their localization in the file. Figure 4. Designing a Control Strategy based on the Quality by Design approach. Figure 5. Synthesis of one CQA Control Strategy (drug substance) and example of localization in the le in CTD format. JANUARY/FEBRUARY 2012 PHARMACEUTICAL ENGINEERING Online Exclusive 5

6 For the Drug Substance (DS): description of manufacturing process and process controls (3.2.S.2.2), control of materials (3.2.S.2.3), controls of critical steps and intermediates (3.2.S.2.4), drug substance specification (3.2.S.4.1), container closure system (3.2.S.6). The evolution of the Control Strategy should be described in the manufacturing process development section of the application (3.2.S.2.6). For the Drug Product (DP): description of manufacturing process and process controls (3.2.P.3.3), controls of critical steps and intermediates (3.2.P.3.4), control of excipients (3.2.P.4.1 and 3.2.P.4.4), drug product specification (3.2.P.5.1), container closure system (3.2.P.7). The evolution of the Control Strategy should be described in the manufacturing process development section of the application (3.2.P.2.3). Additional information linked to evaluation, justification, and future improvement of Control Strategy should be included in the manufacturing process development section (3.2.S.2.6 for DS and 3.2.P.2.3 for DP). Proposal for future management of changes to process parameters and controls is a key for the regulatory flexibility promised to be offered by Quality by Design development approach. Control Strategy as the Keystone of Product Lifecycle According to ICH guidelines Q8, Q9, Q10, and Q11, the lifecycle of Control Strategy is supported by pharmaceutical development (QbD and initial knowledge management), Quality Risk Management (QRM), and the Pharmaceutical Quality System (PQS). Initially developed and implemented during product development for production of clinical trial materials, Control Strategy must be refined when new product/process knowledge is gained during manufacturing of the commercial batches - Figure 6. This improvement helps maintain the link between Control Strategy and product/process understanding. In addition, it helps to optimize the analytical methods by implementation of technical innovations. Effectiveness of the Control Strategy is checked by the first step of process validation (process qualification) performed during technology transfer. Control Strategy (CS) gives the targets for process validation 14 requirements and comparability acceptance criteria. 15 Indeed, during pharmaceutical development, the process design identifies the significant sources of variability. It implements control points and methods to take into account the variabilities and detect their effect, establish the appropriate alert and action limits to ensure that the product CQAs specifications will be achieved. Technology transfer receives these inputs to design and implement the appropriate technologies that answer to the product and process needs and implement the CS. Process validation uses the CS elements ( process controls type and product controls type elements) to demonstrate the process control and the product quality through appropriate acceptance criteria based on the understanding of the product/process links. During the commercial manufacturing step of product lifecycle, Control Strategy appears as a mandatory enabler component for implementation of continual improvement performed under the pharmaceutical quality system. Determining the content of the continuous process verification and providing the components and targets of the product and process monitoring, 14 the Control Strategy sets the path allowing the implementation of continual improvement. Both product and Control Strategy lifecycles are closely linked. On the basis of relevant information provided by data trends collected over time on target parameters and material attributes, the continual product quality can be performed using continous process verification to check Corrective Action Preventive Action (CAPA) and change consequences. 9 In a feedback process, the continuous process verification is a key component assuring the ongoing effectiveness of the Control Strategy. The knowledge gained during product lifecycle on the relevant product/process components enables continual Figure 6. Linkage between product and Control Strategy lifecycles. 6 PHARMACEUTICAL ENGINEERING Online Exclusive JANUARY/FEBRUARY 2012

7 improvement and the maintenance of the Control Strategy, which can be adapted, particularly through update of process models, to the real risks and variability concretely met during manufacturing. Conclusion Control Strategy is required irrespective of the development approach, whatever the process situation toward the Quality by Design approach. It should be defined whether the process/product has been or is being characterized by a QbD approach or the product/process has been developed through a traditional approach. Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach, should have an associated Control Strategy, which can be designed thanks to a combination of both approaches depending on the CQAs and their risk level on patient safety and product efficacy. Control Strategy includes different types of control to assure product quality such as in-process controls and end product testing. For products developed following the minimal approach, the Control Strategy is usually derived empirically and typically relies more on discrete sampling and end product testing. Thanks to product and process characterization under QbD, the Control Strategy is derived using a systematic science and risk-based approach. Risk assessments allow the identification of targets to control among process parameters and in-process materials attributes. These targets are controlled through the elements of the CS. The control points can be shifted earlier into the process and conducted in-line, on-line, or at-line, as the downstream process steps are characterized and understood for their potential additional impact on the final CQAs. Control Strategy overview, detailed scientific justification and rationales of each individual element are presented in the submission file. The continual improvement of Control Strategy is tightly linked to product lifecycle and continual improvement of the product quality, enabled by the pharmaceutical quality system, quality risk management, and knowledge management processes. References 1. ICH Workshop Washington, D.C. Workshop Breakout B: Control Strategy, Davis, B., Lundsberg, L. and Cook, Graham, PQLI Control Strategy Model and Concepts, Journal of Pharmaceutical Innovation, 2008,Vol. 3, No. 2, pp , 3. ISPE Guide Series: Product Quality Lifecycle Implementation (PQLI ) from Concept to Continual Improvement, International Society for Pharmaceutical Engineering (ISPE), First Edition, November 2011, (QbD): Concepts and Principles, including Overview, Criticality, Design Space, and Control Strategy (QbD): Illustrative Example 4. ICH Pharmaceutical Development Q8 (R2), ICH Development and Manufacture of Drug Substances (Chemical Entities and Biotechnical/Biological Entities) Q11 (step 2), Nasr, M., Pharmaceutical Quality for the 21st Century, 2nd Annual QbD Conference in Israel, Rathore, A., and Winkle, H. Quality by Design for Biopharmaceuticals, Nature Biotechnology, January 2009, Vol. 27, No. 1, pp ICH Quality Risk Management Q9, ICH Pharmaceutical Quality System Q10, Implementation of ICH Q8, Q9, Q10, How ICH Q8, Q9, Q10 Guidelines Are Working Together Throughout the Product Lifecycle, ICH Workshop Washington, D.C. Workshop, ICH Quality Implementation Working Group Points to consider ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation, FDA CDER Applying ICH Q8 (R2), Q9 and Q10 Principles to CMC Review. MAPP ICH The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality - M4Q (R1), FDA CDER/CBER/CVM, Process Validation: General Principles and Practices, ICH Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, Q5E About the Authors Johanne Piriou obtained her MSc in biotechnology and biochemistry engineering at National Institute of Applied Sciences of Lyon (France) in She joined Aktehom in 2006 as consultant in pharmaceutical processes control and improvement. She has been involved in transfer technology projects and production start-up of new facilities, as specialist in process design and validation, and knowledge transfer to operational teams. She is senior consultant at Aktehom, specializing in operational implementation of Quality by Design approaches and parenteral drug products manufacturing. Aktehom, 3 avenue Gallieni, Nanterre, France. Bernard Elissondo, PhD obtained his PhD in organic chemistry at the university of Bordeaux (France) in He joined the pharmaceutical industry in 1984, first as head of analytical development and then as R&D manager. After 12 years experience working in the phamaceutical industry, he became a consultant in the CMC area. Based on his broad experience covering CMC technical and leadership roles, he specializes in biotechnological and biological products, particularly in the operational implementation of Quality by Design and its regulatory submission. He is now a Aktehom partner and Scientific Director in charge of product JANUARY/FEBRUARY 2012 PHARMACEUTICAL ENGINEERING Online Exclusive 7

8 development with a special focus on Scientific and Regulatory Affairs. Author of more than 20 publications, Elissondo is a member of PDA. He can be contacted by bernard. elissondo@aktehom.com. Aktehom, 3 avenue Gallieni, Nanterre, France. Michel Hertschuh obtained his Msc in science and manufacturing engineering and joined the consulting company Alphatem in 1995 as business responsible. He continues to have account manager responsibility at Assystem in the parenteral area. He is a partner and co-founder of Aktehom, founded in Since then, he has assumed the responsibilities of development and capitalization and is now Head of Technical Operations. He has spent his entire career in consulting services, primarily for pharmaceutical companies. His expertise is around the aseptic processes, technology transfer, start-up production, and regulatory compliance. He can be contacted by michel.hertschuh@aktehom.com. Aktehom, 3 avenue Gallieni, Nanterre, France. Roland Ollivier, PhD obtained his PhD in organic chemistry at the University of Brest (France) in He worked in different pharmaceutical groups first as chemistry department director and then as R&D manager of the CNS Ddepartment. After 15 years in the pharmaceutical industry, he became manager of two societies specializing in the management of clinical studies and biological screening of drugs in the psychotropic and dependence domains. He is currently the Scientific Manager at Aktehom and specialized in regulatory compliance and Quality by Design implementation through product and process comprehension and risk management specifically in biotechnological domain. He is the author of several publications and patents and he has also chaired a conference in the field of pharmaceutical implementation of the new ICH concepts (Q8-Q9-Q10) for gene therapy products. Aktehom, 3 avenue Gallieni, Nanterre, France. 8 PHARMACEUTICAL ENGINEERING Online Exclusive JANUARY/FEBRUARY 2012