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- 1. Quality by Design VOLUME #1 | SEPT 2016 INVITED GUEST ARTICLE Quality by Design Practices for Contract Development & Manufacturing Organization Ajaz S. Hussain, Ph.D. Insight, Advice and Solutions LLC Today, FDA warning letters, import alerts, and reports of delayed new drug approvals due to manufacturing difficulties continue to dominate trade and general media coverage. Such negative media coverage tends to adversely impact the confidence that the public has in our pharmaceutical quality system. At the beginning of this century, the US FDA launched two initiatives; the Process Analytical Technology (2000) and the Pharmaceutical CGMPS for the 21st Century (2002) to address similar challenges. The phrase ‘Quality by Design’ (QbD), which describes a pharmaceutical I am very excited about the 1st edition of the QbD newsletter. This inaugural edition has informative articles and highlights a few of the successes we have seen in our QbD journey. It is also appropriate that we launch the newsletter at our second annual QbD conference. I hope you enjoy both the newsletter and the conference. Remember, QbD is an important process that enables our promise of “A Healthier World. Delivered”. Patheon’s Quality by Design and Data Analytics program is led by Barry Gujral, who is considered an industry expert in this field. Barry along with a very talented team has created a strong foundation for future success. The program was implemented to provide us and our clients with a greater understanding of the manufacturing process thus assuring product quality. The learning’s and associated improvements made have improved process knowledge and process design. This results in improved product quality, process reliability and ultimately cost savings. Feedback from clients and regulators have been positive. This program is of strategic importance and will assist us in achieving our 5 commitments and becoming preeminent leader in the CMO space. The Quality by Design (QbD) initiative at Patheon is a concept that we promulgate as a core message to all of our sites. The message is that quality should be built into our clients’ products based on the knowledge of target product profile with understanding of characteristics of raw materials and the processes by which the products are manufactured. In a nutshell, the Patheon QbD approach is about communicating meaningful and relevant science upfront to establish post regulatory approval opportunities that will guide continuous manufacturing improvements. Our QbD methodology speaks to real and significant changes in how Patheon, with our clients and regulatory agencies, embraces the regulatory process. But how will this drive the concept of Right First Time (RFT)? What tools are we using at Patheon to achieve RFT? EDITORIAL Driving Right First Time Using Quality by Design Barry Gujral, Ph.D., MBA Global Head of Quality by Design Continued on page 2 Continued on page 4 A message from Harry Gill SVP Quality and Continuous Improvement, Patheon Pharmaceuticals, Inc. A message from Andrew McNicoll VP Quality Systems and Compliance Editorial team
- 2. A Design of Experiment (DOE) approach, in support of quality by design (QbD), was utilized to optimize manufacturing of an advanced intermediate (Compound A) during drug substance synthesis. The optimization was deemed critical in delivering the drug substance with pre-defined quality target product profile (QTPP). A quality risk analysis (QRA) was conducted on the synthetic route to identify the critical process parameters (CPPs) to deliver Compound A with controlled critical quality attributes (CQAs) - impurity profile and yield. Optimization of the CPPs would in turn deliver final purity of drug substance as one of the target product profile specifications relevant for robust product performance. In brief, a DOE approach was utilized to understand the impact of CPPs on CQAs of Compound A. A multivariate analysis of the DOE implied that the acid concentration and a two way interaction between the acid concentration and reaction temperature had a statistically significant impact on the impurity profile of Compound A. Additionally, the reaction temperature had a statistically significant impact on the yield of Compound A. Furthermore, the use of advanced QbD tools, such as, Monte Carlo Simulation and Microsoft Solver allowed establishment of a mathematical predictive model to establish processing ranges leading to a design space for robust manufacturing of Compound A. The robustness of the predictive model was validated by confirmatory experiments that demonstrated successful optimization of CPPs within the design space for manufacturing of Compound A with pre-defined values of impurity profile and yield. This demonstrates that the use of DOE allows all potential impacting factors to be evaluated quickly, simultaneously and systematically. In conclusion, early incorporation of QbD elements in experimental design is highly effective in optimizing CPPs and can be a valuable tool in developing a robust manufacturing process for a drug substance. Use of Design of Experiment in Optimization of Drug Substance Manufacturing Martina Kotthaus, Ph.D. Director R&D Linz Site, Patheon Pharmaceuticals Inc. Early incorporation of QbD elements in experimental design is highly effective in optimizing CPPs and can be a valuable tool in developing a robust manufacturing process for a drug substance. 2 Driving Right First Time Using Quality by Design (continued from page 1) PATHEON’S ROADMAP FOR “RIGHT FIRST TIME” One school of thought is to change ‘Human Behavior’ to achieve RFT. Agreed, changing human behavior is important in achieving RFT. However, is this the only component required to achieve RFT? We need a paradigm shift to the way we develop and manufacture clients’ products in order to minimize human errors. In addition, more automation and computerized systems are being modernized. Multivariate Statistical Process Control is being incorporated where decisions are more data driven rather than human based. These additional steps along with changed ‘Human Behavior’ will facilitate our achievement of Operational and Quality Excellence and ensure the desired state of ‘Right First Time’. Patheon will embrace the principles of QbD to drive RFT by designing a solution that is both pragmatic from a compliance standpoint and flexible from a business perspective. We have achieved positive results by implementing a traditional quality risk management system. However, to achieve RFT, some additional steps including the implementation of automation with QbD need to be taken. Patheon is working very diligently to apply the tools of QbD. Patheon QbD group recommends a roadmap to achieve ‘Right First Time’. Due to limited space, I am providing a summary of the vision of the roadmap. We are working on a number of new products being developed under QbD. Additionally, we are continuously improving commercial products at multiple Patheon sites using QbD. Our initiatives on implementing QbD guidelines and standards along with QbD training will help to ensure RFT at all sites.
- 3. For manufacturing biologics, process characterization is a critical phase in the development of a commercial process. Here, we use a Quality by Design approach for the characterization of an upstream fed-batch cell culture process to express a monoclonal antibody. For this molecule, the glycosylation profile, and in particular, the total fucosylation was identified as a CQA. After performing a primary hazard analysis, several process inputs were determined to potentially have an impact on this CQA. These parameters were then studied in a screening DoE using the ambr15™ to model the first and second order effects for each parameter on the CQAs and process performance. Forty-eight different conditions were tested in a single 2-week run. Five parameters demonstrated a statistically significant effect on the fucosylation of the molecule and six demonstrated a significant impact on process performance. A design space was determined to establish the proven acceptable range (PAR) for each parameter. Monte-Carlo simulations were performed and it was determined that >5% of the batches could potentially exceed the specification limits on product quality. Further, a set point adjustment was recommended for two of the settings. With these new settings, the simulations showed 100% of the potential batches to pass specification. Through the use of high throughput technology and Monte-Carlo simulations we have been able to reduce timelines, improve process robustness and determine key and critical process parameters for phase III process characterization. Critical Process Parameter Identification Using the Ambr15™ for Process Characterization Matthew Zustiak, Ph.D. Manager upstream process development, Patheon Biologics The FDA guidance documents1 are very clear about the need to develop analytical test methods using analytical chemistry principles along with challenging the robustness of the test method using a design of experiments approach. This is a sound development approach and will lead to more reliable and accurate test methods. For methods we develop at Patheon, we are obligated to follow this process and generate robust methods with sound analytical chemistry. However in the PDS environment, we receive projects from customers in all stages of development, from pre-clinical to Phase III registration batches. To consistently evaluate methods and provide quantitative feedback to our customers, PDS-Analytic Development (PDS-AD) has implemented a Method Risk Assessment process for all new methods coming into our development groups. We include a slide about the method risk assessment in our project kick-off meeting. We highlight these elements with our customers. • Prior to initiation of method transfer / implementation for chromatographic analytical methods, a ‘paper based’ method Risk Assessment should be performed. • Serves as both a ‘knowledge transfer’ document and a tool for identifying areas of concern / potential improvement prior to use in a GMP setting. • Risks are evaluated on specific method parameters and classified based on potential impact and likelihood of occurrence. We use a matrix of likelihood and impact to determine a quantitative rating for method risk that is developed from an extensive checklist of attributes. The risk evaluation tool includes assessment of sample preparation, chromatographic separation, data interpretation, and an overall summary. Our experience to date is that customers react positively to this structured approach, and in some cases based on using this tool, they have agreed to fully re-develop their existing methods. We have also provided this risk assessment tool to our Tech Transfer colleagues, and we will begin to apply this approach to existing product test methods. In summary, PDS-AD is using the Risk Assessment element of the QbD strategy to consistently and quantitatively evaluate test methods. Our customers also receive significant added value to their product from this structured approach. Quality by Design in PDS Analytical Development William E. Weiser, Ph.D. Global Head of Analytical Sciences, PDS, Patheon Pharmaceuticals Inc. = 1 “Analytical Procedures and Method Validation for Drugs and Biologics”, Guidance for Industry, US FDA, July 2015, Pharmaceutical Quality/CMC. 3 DESIGNING QUALITY IN DAILY LIFE
- 4. product development method-ology, emerged from these initiatives and is now formalized in the ICH Q8 guideline. Several other guidelines, specifically the 2011 Guidance on Process Validation, incorporate this methodology by reference to the PAT and the ICH Q8 guidelines. In late 2015, the FDA reorganized to bring a more focused effort on “One Voice of Quality”. These recent efforts are, in part, to fully realize the benefits of the approaches outlined in the initiatives that were launched more than a decade ago. What does this all mean for a contract development and manufacturing organizations (CMOs)? Beyond the traditional services, which intend to fill the gaps a client may have in technical and infrastructure capacity, CMOs can/ should play a significant role in preventing erosion of public confidence. CMOs can play this role via helping clients overcome the deficiencies that may exist in their product development and in the quality assurance practices. To do so, CMO’s need to acquire a deeper understanding of the issues underpinning the following three questions: • Why haven’t the FDA initiatives (mentioned above) helped address the noted challenges? • What are the objectives of the FDA’s latest program on “One Quality Voice”? • How can a CMO contribute to strengthening confidence the public should have in our quality management system? The article published separately will share insights gained by the author while leading the FDA initiatives (2000-2004) and the experience in the industry (2005-currently) – particularly from developing and conducting an industrial training program on Culture of Pharmaceutical Quality (2014-2016). Quality by Design Practices for Contract Development Manufacturing Organization (continued from page 1) +1 866 728 4366 • www.patheon.com • doingbusiness@patheon.com As we embark on our Continuous Manufacturing journey at Patheon, we quickly realize what a game changer this technology platform is for us. In this platform, we can realize the paradigm shift that started over 15 years ago with the 2002 FDA initiative “Pharma- ceutical GMP for the 21st Century”. The FDA and industry moved toward risk based lifecycle approaches to the development and commer- cialization of pharmaceutical products. This lifecycle approach refined the way we considered validation - the FDA validation guidance of 2011 referenced Quality by Design principles and established stage 1 (Process Design), stage 2 (Process Qualification), and stage 3 (Continued Process Verification- CPV) as the new lifecycle approach requirement. Continuous manufacturing technology together with PAT enabled the implementation of automatic real time monitoring and control of critical process parameters and critical quality attributes as desired by QbD. Stage 1 validation and process design can now occur on the commercial process train since continuous manufacturing equipment trains require reduced footprint and integrated unit ops in one system. In Stage 2 validation we are qualifying the developed process on the same train as used for development studies, thereby saving precious time, material, and money. In stage 3, we can use multivariate data analysis on reams of process data to verify the maintenance of our product in the validated state, and use the increased process understanding to fuel opportunities for ongoing process optimization and improvement. Thus, QbD and Continuous Manufacturing represent a paradigm shift that promises to change the drug manufacturing landscape for years to come. Quality by Design Continuous Manufacturing at Patheon Stephen Closs VP Global Tech Ops, Patheon Pharmaceuticals Inc. For more information, please contact: Barry Gujral, Ph.D., MBA Director, Quality by Design Cell: 919-316-8115 barry.gujral@patheon.com GLIMPSES FROM FIRST QbD CONFERENCE 2015