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This article provides an overview of validation concept principles evolution to a life cycle risk-based approach with focus on compendial perspectives.
In recent years, regulatory agencies have placed an increased emphasis on pharmaceutical process understanding through adoption of Quality by Design (QbD) principles by launching a series of initiatives to encourage the pharmaceutical industry to adopt QbD in the manufacturing process. A key component of this transformation is the evolution of validation concepts to a life cycle risk-based approach driven by Analytical Quality by Design (AQbD) principles. Different pharmacopoeias have been developing compendial approaches to support the implementation of analytical procedure life cycle (APLC) risk-based approach. Additionally, the International Conference on Harmonisation (ICH) released in March 2022 two draft guidelines for public consultation which outline QbD principles: ICH Q14 (procedure development) (1), and the ICH Q2(R2) (procedure validation) (2). In a series of two articles, the authors will provide an overview of the validation concept principles evolution with a focus on compendial perspectives (Part I) and draw a parallel between ICH Q14 and Q2(R2) and United States Pharmacopeia (USP) General Chapter <1220> and the ISO/IEC 17025:2017 (Part II).
The new industrial revolution, “Industry 4.0,” has been leading to changes in the pharmaceutical industry (“Pharma 4.0”), where significant paradigm shifts have been occurring in the pharmaceutical quality environment to enable manufacturing modernization and innovation. These changes have significant implications for how we think about pharmaceutical quality. Regulators, industry, and standards-setting organizations are increasingly recognizing the need to rely more on risk-based and QbD approaches rather than ensuring quality solely by compliance-driven and quality-by-testing approaches (3). In this context, traditional validation practices are undergoing a paradigm shift that requires an in-depth understanding of products and processes.
The principles of process validation were initially established in the US Food and Drug Administration (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 promulgated 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 clinical studies, in preparation for filing biologics license application (BLA)/new drug application (NDA) and commercialization of the product. Validation activities conducted 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 paradigm based on QbD principles started to take shape with the goal of building the quality into the product.
QbD is a concept first developed by the quality pioneer Dr. Joseph M. Juran (6). As defined by Dr. Janet Woodcock, currently FDA’s principal deputy commissioner, “QbD means that product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically 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 initiatives 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 outlining 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 principles were outlined in the process validation guidance published in 2011 by FDA (12) and in 2012 by the European 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 development 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 transformation of quality culture, launching a series of pilot programs since 2005 to incorporate elements of QRM and QbD throughout the product life cycle (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 regulatory 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 analytical procedures)(17) and ICH Q13 draft guideline (continuous manufacturing) (18). ICH also established an Expert 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 quality culture transformation necessary for continuous quality improvement, FDA continues to work on strategies to support implementation of product life cycle principles and facilitate regulatory flexibility when evidence of a mature and effective quality system is available (19). Investigations of supply disruptions show that manufacturing 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 Protocol Project (NIPP) and Quality Management Maturity (QMM) (20) programs are examples of initiatives led by the 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).
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 and controlling sources of variability (8). Furthermore, existing guidance is often applied in a checkbox manner, and default performance criteria are often established to satisfy compliance objectives, although the rationale for establishing the criteria is not always transparent. In other words, often no proper performance requirements are established to ensure fitness for use.
In 2013, USP created the USP Verification and Validation Expert Panel (EP) to envision the future of analytical validation concepts. Later, this Panel became the USP Measurement & Data Quality Expert Committee. Several USP stimuli articles were published from 2013 to 2019, covering key aspects of the APLC. These include:
These articles incorporate QbD principles previously outlined in ICH Q8-Q12 and in publications by different associations such as the joint working groups of the European Federation of the Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) (7,27). These articles built the basis for developing USP General Chapter <1220> Analytical Procedure Lifecycle, published in PF46(5) Dec. 1, 2020 (official as of May 1, 2022, in USP-National Formulary). USP <1220> presents a holistic approach for APLC management and highlights the importance of sound scientific approaches and QRM for the development, control, establishment, and use of procedures to ensure fitness for use (28). The APLC approach is considered an enhanced approach driven by AQbD principles that provides connectivity between all stages of the APLC, allowing for proper knowledge management.
“Analytical Quality by Design (AQbD) is asystematic approach to development that begins with predefined objectives and performance requirements (analytical target profile) and emphasizes procedure performance understanding and control, based on sound science and quality risk management. AQbD is derived from QbD principles and refers to the application of QbD in the APLC management allowing for the quality to be built into the procedure design.”
The major driver for adopting the life cycle approach is to ensure that the reportable value is fit for use, because the reportable value provides the basis for key decisions regarding compliance of a product with regulatory, compendial, and manufacturing limits (28).
Key questions that the industry usually needs to answer are:
By ensuring analytical procedure (AP) fitness for use, the industry is allowed to answer these questions with confidence and minimize the risk of making the wrong decision about the product’s conformance and quality. In USP <1220>, fitness for use is described as a concept used to show that a procedure meets established performance requirements and is considered fit for its intended purpose, where the establishment of the acceptable probability of making a wrong decision is part of ensuring that the AP is fit for use (28).
Different approaches can be used to ensure procedure fitness for use. Along the evolution of AP validation concepts, the acquisition of understanding about total procedure variability and its association with risk of false conformity/nonconformity decisions about pharmaceutical products has been reinforced (26). Thus, a central piece of the APLC approach involves the consideration of measurement uncertainty (MU)/total analytical error (TAE) as a critical procedure attribute to guide AP design, establish acceptance criteria for procedure qualification, and guide the ongoing procedure monitoring phase. Concepts such as analytical target profile (ATP) and maximum allowable MU (i.e., target measurement uncertainty -[TMU]) have been introduced to draw attention to fitness for use as a goal throughout the analytical life cycle (26). The APLC framework is depicted in Figure 2.
Key elements and stages are as follows:
Despite the existing ICH guidelines Q8–Q12 outlining QbD principles applied to drug development, AP are not considered in their scope, although all the concepts apply to APLC. The early development of compendial approaches and capability building activities by USP has been helping to pave the way for the transformation of the quality culture based on new quality paradigms. USP, together with other worldwide organizations/associations, has been promoting the AQbD principles that may transform the quality culture by enabling and supporting innovation for both small molecule and biological medicines (7,27–29). The British Pharmacopoeia (BP) has also been playing an important role in this transformation. In 2014, an AQbD working party was established and a new supplementary chapter “Application of AQbD to Pharmacopoeial Methods” was published in BP 2022 (30). In 2019, a consultation was also published by BP and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) to explore the inclusion of AQbD elements in compendial monographs and the consultation response became public available in 2020 (31). A case study was also published in 2019 with focus on the practical application of AQbD principles to the development of an assay procedure for atorvastatin in atorvastatin tablets (32). The atorvastatin tablets monograph was published in BP 2023 including two AQbD elements (ATP and MODR) as non-compendial tools. USP is also working on creating practical case studies to explore how AQbD elements may be included in monographs in the future, with the aim to provide the industry with additional knowledge for proper procedure performance verification and QRM, allowing for continuous quality improvement. USP and BP chapters are informational chapters and aim to provide guidance for the implementation of enhanced approaches to support APLC management. The European Pharmacopeia launched in 2022 a call for volunteers for a new working party on AQbD (33). The APLC concept also underlies the standard ISO/IEC 17025 (34). Figure 3 shows the evolution of QbD considering relevant guidelines.
FDA has not provided specific guidance on how to implement the APLC approach, however, chapter VIII of the FDA guidance on AP validation published in 2015 (35) mentions the life cycle management of AP and highlights the importance of trend analysis for procedure performance and use of risk assessment for procedure development and validation.
A few other existing USP general chapters cover principles and considerations for some stages of the APLC (e.g., <1225> Validation of Compendial Procedures (36), <1226> Verification of Compendial Procedures (37), <1224> Transfer of Analytical Procedures (38), <1210> Statistical Tools for Procedure Validation (39), <1039> Chemometrics (40), and <1010> Analytical Data - Interpretation and Treatment (41)). USP <1010> includes statistical approaches for procedures comparability (e.g., equivalence of means and noninferiority of variabilities) that can be used to support risk assessment and evaluation of performance equivalence for procedure transfer and analytical conditions changes supporting change management and procedure qualification. These statistical approaches for procedures comparability are also cited in the current version of the FDA guidance on procedure validation, chapter VIII.B (35). The USP chapters mentioned previously do not consider currently the connectivity between the different APLC stages and may be reviewed in the near future. Although USP <1220> provides a holistic approach to manage the APLC, it does not provide clear guidance for multivariate procedures development and connectivity with the multivariate model life cycle, which is described at a high-level in USP <1039>. Building the interconnections between both of these chapters would facilitate the development of enhanced control strategies using online/at-line/in-line PATs to support the implementation of innovative manufacturing approaches such as continuous manufacturing and real time release testing (RTRT). Currently, USP <1039> has a greater focus on spectroscopic applications and may also be revised to allow the expansion of its scope to other techniques and applications.
In the ICH Q guideline series, Q14 is the first to address approaches for procedure design and is similar to stage 1 and 3 according to USP <1220>. Q2(R2) can be seen, at least in part, as similar to stage 2 described in USP <1220>. In contrast to the framework described in USP <1220>, ICH Q14/Q2(R2) EWG split both topics, attempting to keep the status quo and avoid a drastic change to the structure of Q2(R1). Although Q14 and Q2(R2) represent great progress toward implementation of sound science and QRM, their publication as separate documents still leaves some gaps because a comprehensive and continuum APLC is not presented. These draft guidelines also discuss little or nothing about essential APLC elements (e.g., Q2(R2) does not include ATP and Q14 does not emphasize ongoing performance verification). Similarities and differences between USP <1220> and Q14/Q2(R2) and their implications are discussed in Part II of this article.
In sum up, the APLC framework is considered as an enhanced approach and represents the evolution of AP validation concepts that may likely replace traditional/minimal approaches in the future since it offers several advantages. These advantages include development of more robust and optimized procedures, increased reliability of deciding whether a product is conforming or out-of-specification and regulatory flexibility for post-approval changes. Furthermore, APLC and AQbD could drive innovation and the continuous improvement of quality based on risk/knowledge management.
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Amanda Guiraldelli is scientific affairs manager at the United States Pharmacopeia. Jane Weitzel is an independent consultant and chair of the US Pharmacopeia Expert Committee on Measurement and Data Quality.