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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 27 Validation data set processing and analysis. Q2(R2) builds off ex isting principles described in Q13 (continuous manufacturing) (18) and supports the development and validation of not just off line procedures but also in-line/online/at-line procedures that can be used for process monitoring/control and RTRT. USP <1039> Chemometrics provides general guidance on the ap- plication of machine learning algorithms in the de- velopment of multivariate procedures; however, it does not provide connectivity to the APLC described in USP <1220> and may be revised in the near future to provide best practices for development of PATs and to cover a wider spectrum of analytical techniques. USP <1039> may also be used as a risk-based approach for development of different compendial standards, along with USP <1220>. Performance characteristics at a glance In ICH Q2(R2), the language around a few perfor- mance characteristics was changed to accommodate suitable considerations for the validation of uni- and multi-variate procedures. Table III provides a sum- mary of these changes. Drawing parallels between ISO standards, ICH Q14/Q2(R2), and USP <1220> The evolution of validation concept principles to a APLC risk-based approach is also occurring in other industries, standard-setting bodies, and regulations. Consequently, they are incorporating similar tools and approaches, often taking these from metrology. In this section, the approaches of the ISO standards, especially ISO/IEC 17025:2017; the ICH Q14/Q2(R2); and USP <1220> are presented and compared (Tables IV and V). They may use different terms or emphasize various related concepts differently, but they all have this same focus: "ensure that a procedure is fit for use." Another similarity between these guidelines is the importance of assessing risk. Risk is based on fit for purpose, because risk is assessed by its impact on the analytical procedure's fitness for purpose. In addi- tion, probability is part of risk, where the probability TABLE IV. Comparison of terminology and elements between International Council for Harmonisation (ICH) Q14, Q2(R2), United States Pharmacopeia (USP) <1220>, and International Organization for Standardization/International Electrotechnical Commission (ISO/IEC) 17025–Part I. GUM is Guide to the Expression of Uncertainty in Measurement. Concept ISO ISO/IEC 17025 ICH Q14&Q2(R2) USP <1220> Fit for purpose ISO focuses on the needs of the customer. For analytical chemistry, this includes the client's use of the reportable value. The GUM in its definition of true value states that it must have an uncertainty appropriate for a given purpose. ISO 9001 is based on seven quality management principles (QMP), of which the first is Customer Focus. "7.2.2.3 The performance characteristics of validated methods, as assessed for the intended use, shall be relevant to the customers' needs and consistent with specified requirements." "fit for its intended purpose: to measure an attribute or attributes of the analyzed material with the needed specificity/ selectivity, accuracy and/ or precision over the reportable range."(Q14) Demonstration of meeting the intended use as specified in the analytical target profile (ATP) through the analytical procedure life cycle (APLC). Risk ISO has many standards dealing with risk, including the ISO 31000 family of standards relating to risk management. The risk-based thinking has enabled some reduction in prescriptive requirements and their replacement by performance-based requirements. Q9/Q14 addresses risk extensively. Addresses risk extensively. Accuracy and Precision Included in many ISO standards (e.g., ISO 14253-1:2017). Decision rules are included, and their use is required by ISO/IEC 17025:2017 7.8.6. Decision rules are not mentioned explicitly in Q2 or Q14 but can be used to achieve requirements. Decision rules are included. Probability For example, ISO 3534-1:2006 Probability is part of decision rules. Probability is mentioned under risk. USP <1210> addresses probability. ATP Not included. ISO does require clear, concise, specific understanding of the customer's needs. The ATP is one mechanism to achieve this. Although the components of an ATP are included (e.g., target MU, probability) the concept of ATP is not included. Included in Q14, but not in Q2(R2). Included. Focus on the fit for purpose of the reportable value.