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16 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com Validation paradigm shift that requires an in-depth understand- ing of products and processes. The principles of process validation were initially established in FDA guidance on general principles of process validation in 1987 (4) and have been considered in guidelines worldwide, including the current good manufacturing practices (CGMP) regulations promul- gated by European regulatory agencies and the ICH. At that time, a common validation practice was to conduct process validation activities during the late stages of the product life cycle, primarily during Phase III clin- ical studies, in preparation for filing biologics license application (BLA)/new drug application (NDA) and com- mercialization of the product. Validation activities con- ducted at early stages were minimal (5). Since 1987, the concepts of validation have evolved from a traditional "fixed-point" manufacturing process to a "life cycle" risk-based approach (5). Gradually, a new quality par- adigm based on QbD principles started to take shape with the goal of building the quality into the product. QbD is a concept f irst developed by the qualit y pioneer Dr. Joseph M. Juran (6). As defined by Dr. Janet Woodcock, currently FDA's principal deputy commissioner, "QbD means that product and pro- cess performance characteristics are scientifically designed to meet specific objectives, not merely em- pirically derived from performance of test batches" (7). Over the past 20 years, regulatory agencies have been encouraging the adoption of QbD principles in pharmaceutical development through several initia- tives including the FDA 2004 report, "Pharmaceutical cGMPs for the 21st Century–A Risk Based Approach" (8). The need to modernize the quality management process was also recognized by ICH and resulted in the development of a new series of guidelines outlin- ing QbD principles and emphasizing the importance of knowledge and quality risk management (QRM)(9). In the ICH Q guideline series, the QbD concept was first introduced in 2004 in the ICH Q8 Pharmaceutical Development (10). The notion of QRM's importance as an enabler of the QbD approach was reinforced with the approval of ICH Q9 in 2005 (11). Later, QbD princi- ples were outlined in the process validation guidance published in 2011 by FDA (12) and in 2012 by the Eu- ropean Medicines Agency (EMA) (13), which are now in line with ICH Q8–Q11; both also require adherence to CGMP regulation. "Quality by Design is a systematic approach to de- velopment that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" (10). FDA has played a pivotal role in the transforma- tion of qualit y culture, launching a series of pilot progra ms si nce 2005 to i ncor porate elements of QRM and QbD t h roughout t he product life c ycle (e.g., FDA ONDQA CMC pilot program 2005 (14); FDA OBP pilot program 2008). In March 2011, EMA and FDA launched a pilot to assess QbD applications in order to ensure consistent implementation of ICH Q8–11 guidelines between the European Union and the United States and facilitate sharing of regula- tory decisions on new regulatory concepts (14,15). A final report was issued to communicate the lessons learned from the program (16). ICH continued to develop guidelines outlining QbD principles. Examples are ICH Q12 (holistic framework for product life cycle management including analyti- cal procedures)(17) and ICH Q13 draft guideline (contin- uous manufacturing) (18). ICH also established an Ex- pert Working Group (EWG) in 2018 to revise Q2(R1) and develop the new guideline Q14 covering approaches for analytical procedure development. Q14 and Q2(R2) were released for public consultation in March 2022, outlining the life cycle risk-based approach applied to APLC management. These guidelines also build off both Q12 and Q13 guidelines, providing support to allow for implementation of principles and concepts described in both guides (Figure 1). To advance the qualit y culture transformation necessary for continuous quality improvement, FDA continues to work on strategies to support implemen- tation of product life cycle principles and facilitate regulatory flexibility when evidence of a mature and effective quality system is available (19). Investiga- tions of supply disruptions show that manufactur- ing or quality issues are common root causes of drug shortages (e.g., substandard manufacturing sites or processes, or quality defects in the finished product), highlighting the need to implement strategies that can help advance quality. The New Inspection Proto- col Project (NIPP) and Quality Management Maturity (QMM) (20) programs are examples of initiatives led by FDA to build a framework to enable continuous quality improvement and mitigation of quality risks. In the 2021 report on the state of pharmaceutical quality, FDA recognizes that enhanced knowledge management and emphasis on risk-based approaches will enable FDA to target its regulatory resources more effectively, better protect the public from noncompliant products, and advance the quality of medicines (19). The NIPP and QMM initiatives demonstrate FDA's commitment to innovative quality programs (19). Evolution of validation concept in the analytical procedure context: analytical procedure life cycle The concept of analytical procedure validation has also been evolving to a life cycle risk-based approach. Current validation practices often focus on satisfying regulatory requirements rather than understanding