Edition 4 / December 2020
Dr. Iris Ziegler,
Director of Pharmaceutical Sciences & QbD,
Quality by Design (QbD) was introduced to the Pharmaceutical world in 2004, when ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Considerations) first published Pharmaceutical Development ICH Q8 in an effort to step up Drug Product development to standards based on scientific understanding of products, manufacturing processes, systematic risk management and continuous improvement. A further update of the guideline was published in 2009 (ICH Q8 (R2)).
Those principles, which had already been recognised for many years in other industries – then called Design for Six Sigma – now finally signalled the dawn of a new age for Pharma. They moved away from its traditional development approach, which relied heavily on the old paradigm of quality testing and assuring via GMP requirements, towards a new mindset of designing for quality with consistent risk-based life cycle management, improved processes, and product understanding as the main drivers.
Since then, many other guidelines have endorsed this new paradigm of QbD, extending it beyond drug products to drug substances, including biologics and even excipients. In 2019, ICH Q12 extended the principles of QbD also to the life cycle management of pharmaceutical products. By the time ICH Q14 is adopted in 2021, this approach is expected to be implemented for the development of analytical methods as well.
Over these last decades, QbD has now finally evolved into the new way of approaching development in Pharma. Initially many companies were struggling with this holistic approach, which requires implementation during early phases of development, far before GMP regulations apply. It also extends QA oversight to those phases in line with ICHQ 10 (Pharmaceutical Quality System Q10).
Today, most companies have adopted at least parts of the QbD driven development philosophy and are using systematic, science-based investigations and development tools such as Design of Experiment (DoE) or Process Analytical Tools (PAT) for real time non-destructive in-line measurements during their development and scale-up activities. The concept of QbD is widely acknowledged as best practice in terms of outcome, as evidenced by the fact that this customer-centric pharmaceutical development approach has even made it into Wikipedia. However, a systematic Quality Risk Management (QRM) process in line with ICH Q9 (Quality Risk Management Q9) and ICH Q10 guidelines throughout all development activities, even outside the GMP environment, is an area where many companies are still struggling.
The implementation of systematic multi-project and multi-phase risk management throughout all development and life cycle activities presents many challenges, not the least of which is suitable software tools for assessment, evaluation, review and communication of the risks and knowledge gained throughout the projects. This often-overlooked aspect can be a major obstacle to implementation spanning all activities from start to finish, causing massive blockage of team resources, delays in project kick-offs, and frustration resulting from the management of huge Excel lists.
We therefore see an increasing need for intelligent software solutions that provide the most tangible benefits in overcoming these obstacles. In helping to implement a systematic QRM approach, while staying flexible enough during early development phases and not being limited to the classic FMEA (Failure Mode Effect Analysis) approach, such intelligent software solutions facilitate the rollout of QbD & QRM and greatly boost the visibility of the perceived benefits. FMEA originates from an engineering environment, and although widely established, it is often much too rigid for early-phase process development or formulation screening. On the other hand, we need to collect important knowledge and learnings already during these early phases to understand and optimise processes & product quality. Therefore, risks have to be managed and captured during early development just as systematically as throughout later phases. Ideally, all information gained should be transferred automatically into the next phase, making it easier for the team to set up risk assessments and directly benefit from the knowledge gained in past projects.
Quality Risk Management is a key enabler for Quality by Design (QbD) driven development, as it allows for a systematic, risk-based approach in deciding which quality attributes are most critically impacted by material attributes and process parameters, and helps determine what must be addressed most urgently at each phase of the development. The objective of a QbD approach is to ensure that the development plan results in a “product”* fulfilling the quality expectations required for the current stage of development, and that the final process at commercial scale will consistently produce a “product” fulfilling all Critical Quality Attributes, enabling Continuous Improvement throughout Life Cycle Management.
QbD is thus both a quality and business initiative, providing the ability to schedule supplies and processing just in time, since applying a well-understood and well-controlled manufacturing process ensures the desired quality outcome, instead of having to wait for final QC testing. These advantages greatly improve efficiency and operational excellence, while reducing overall costs of manufacturing and supply.
As a CDMO, CordenPharma strives for superior customer satisfaction by delivering high quality products at competitive manufacturing costs in compatible timelines. One of the many factors behind our customers’ level of satisfaction is our focus on prioritizing a sound Quality Risk Management Process throughout all projects from kick-off to completion, with an attitude of “doing the right things at the right time to get it right first time” instead of investing valuable time and resources on tasks deemed less urgent based on our knowledge from the risk management process.
Our complex business, with multiple facilities, products, and processes running in parallel, requires a systematic and harmonised quality approach that ensures seamless project management and tech transfer in different phases of development using harmonised tools and language throughout our globally integrated facility network. Although each site, project, and process is different, we utilize an infrastructure of Knowledge Management that allows for proactive and transparent sharing of expertise and learnings from past and current projects. Additionally, the ability to review and assess the effectiveness of risk mitigations and outcomes from similar past projects for new ones increases overall efficiency and effectiveness of development activities, as well as the Life Cycle Management of commercial products.
iRISKTM from 4Tune Engineering Ltd is a software-based Quality Risk Management tool that allows for systematic set up, review and reporting of a QRM process in compliance with ICH Q9 and ICH Q10 for all stages of development and life cycle management. This intelligent technology provides different workflow tools and ranking systems that can be configured for each phase. The software guides users through the setup of new risk folders, risk assessment & evaluation of critical inputs on the Critical Quality Attributes (CQAs), and overall process performance. Appropriate actions and a Control Strategy are defined based on the effectiveness of actions to reduce risks. All steps benefit from the continuously increasing knowledge in the database, which is offered to identify risks, CQAs, inputs and actions, as well as a harmonised language for generating new risk folders. The software is fully compliant with CFR Part 11, and also supports GMP workflows and approval processes. The visualisation of both the progress and outcome of risk management activities enables project managers to monitor their efforts and project performance, QA managers to perform development oversight, and senior management to obtain an overview on the criticality of projects and the effectiveness of proposed mitigations during management review.
After an initial evaluation of requirements, available options and intensive testing during a trial phase, CordenPharma made the decision in June 2020 to acquire and adopt this software as the standard for QRM during development and life cycle management at all CordenPharma sites. The first group of users were trained in September, the second in November, and an overall objective is set to be have the software fully validated by mid of 2021. A team of super users comprised of members from all CordenPharma sites performed the configuration of settings and generated harmonised templates, workflows and rankings in the software, which are to be used by all users.
iRISKTM was rolled out in CordenPharma’s R&D and Project Management with 62 initial licenses, but additional licenses are planned for 2021 as more users and groups are added. The software can also be applied to assess the risks and validate the state of commercial products throughout Continued Process Verification.
Using iRISKTM intelligent software for Quality Risk Management throughout development and Life Cycle Management for our customers’ “products” is an important step towards the implementation of a systematic, science-based and risk-driven Quality by Design approach at CordenPharma, and an important aspect of our positioning as a leader in quality and customer satisfaction.
* “product” means both drug compounds and drug products
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