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26 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com Validation Knowledge management versus checkbox exercise: incorporation of risk-based approach principles ICH Q2(R2) empha sizes t he i mpor ta nce of usi ng prior knowledge to design the validation protocol and illustrates the interdependencies of APLC stages covered in Q14. The ATP is an element considered as a guide to ensure fitness for use along the entire APLC in USP <1220>. However, the ATP was not men- tioned in Q2(R2), which still leaves some gaps in en- suring fitness for use and representing the APLC ho- listically. A new section entitled "Validation during the lifecycle of an AP" was included to emphasize t he i m p or t a nce of A P L C m a n a ge me nt . Q2(R 2) mentions that changes may be required during the product life cycle and that science- and risk-based principles can be used to justif y whether or not a given performance characteristic needs revalida- tion. This provides connectivity to Q14 (section 7), which is in line wit h Q12, and prov ides a cer tain f lexibility for submission of post-approval changes by the industry. Amplify spectrum of analytical techniques and support validation of RTRT While ICH Q2(R1) places a greater focus on chromato- graphic procedures and is not sufficient to establish the suitabilit y of multivariate procedures, Q2(R2) amplifies the spectrum of analytical procedure that it can be applied to, such as UV (entire spectrum), infrared spectroscopy (IR), near-infrared spectros- copy (NIR), nuclear magnetic resonance (NMR), mass spectrometr y (MS), liquid chromatography-mass spectrometry (LC-MS), etc. The new section, 3.4, in Q2(R2) provides considerations for validation of mul- tivariate analytical procedure. This supports devel- opment of process analy tical technologies (PATs), which usually apply multivariate data and require the use of machine learning methodologies for large TABLE III. Comparison of performance characteristics described in International Council for Harmonisation (ICH) Q2(R1) and Q2(R2) and how they relate to United States Pharmacopeia (USP) chapters and ICH Q14. Typical Performance Characteristics in Q2(R2) Comments Drawing a parallel to existing USP chapters Connectivity with Q14 Specificity/Selectivity Q2(R1) mentions only specificity. Q2(R2) mentions both specificity and selectivity, enlarging the applicability of Q2(R2) to other techniques since multivariate techniques usually provide complex data sets containing signals related to several variables. Q2(R2) emphasizes that specificity/ selectivity should be demonstrated to fulfill the accuracy requirements by showing unbiased measurement of target compounds individually and/or from other components in the sample matrix. This may trigger the review of USP <1225>. Working Range: Linearity, Range, Quantitation Limit, and Detection Limit in Q2(R1) In Q2(R2), "Linearity" has been removed and became a broader concept called "Working Range", including: • Suitability of Calibration Model (Linear Response, Non-Linear Response, and Multivariate Calibration) • Lower Range Limit Verification, including Quantitation Limit (QL) and Detection Limit (DL) This may trigger the review of USP <1225> and development of stimuli articles. Accuracy and Precision Q2(R2) presents a combined approach that can be used as an alternative to evaluating accuracy and precision separately, while Q1(R1) presents only individual assessment of accuracy and precision. Combined approach is consistent with USP <1210> Statistical Tool for Procedure Validation (published in 2018). <1210> Section 3.2 provides examples of combined validation of accuracy and precision using prediction and tolerance intervals. This provides connectivity to the term included in Q14, "Total Analytical Error (TAE)," since prediction and tolerance intervals are a few approaches that can be used to estimate TAE. In Q14, TAE is considered an alternative approach that may be used to establish performance requirement to be included in the ATP.