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18 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com Validation • "Can the lot of finished product meet specifica- tion so it can be released?" • "Does the manufacturing in-process sample contain the right amount of excipient?" • "Is the concentration of a residual solvent low enough to meet regulatory requirement?" • "W hat is t he concent rat ion of d r ug i n t he blood from a clinical study so that the dosage can be established?" 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 estab- lished 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 proce- dure fitness for use. Along the evolution of AP valida- tion 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 pro- cedure monitoring phase. Concepts such as analyti- cal 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: ATP is the predefined intended purpose of the pro- cedure that stipulates what procedure performance requirements are that are linked to the intended an- alytical application and the quality attribute to be measured (28). This includes the definition of the required qua lit y of t he repor table va lue, a ligned with the quality target product profile (QTPP). For quantitative or semi-quantitative procedures, the ATP should include upper limits on the precision and accuracy (bias) of the reportable value (28). The ATP ca n be rev iewed whenever necessa r y, based on knowledge acquired and risks identified during other stages of the APLC. Stage 1 Procedure Design a i ms to acqui re un- derstanding of how analytical parameters impact critical procedure attributes. The QRM process is wh at d r ives t he desig n of opt i mu m cond it ion s, a l low i n g t he ide nt i f ic a t ion of cond it ion s t h a t optimize performance and minimize/avoid bias (re- ducing variability) to establish an operating range ca l led "met hod operable design region" (MODR). The MODR is a multidimensional region where all study factors in combination provide suitable mean performance and robustness, ensuring procedure fitness for use. The MODR is equivalent to the term "Design Space" cited in the ICH Q8. Stage 2 Analytical Procedure Performance Qual- ification (APPQ), as per USP <1220>, refers to all ac- tivities conducted during stage 2 to confirm that the procedure is fit for its intended purpose and meets the requirements of the ATP. This stage may include the traditional procedure validation, transfer, and verification (28). USP <1220> brings together both concepts of "APPQ" and "AP Validation," where "AP validation" is a broader concept that encompasses all activities that confirm that a procedure is suit- able for the intended purpose; these activities take place over the entire APLC, not only under stage 2 (28). This differs from the current definition of AP validation described in ICH Q2(R1) and Q2(R2). Stage 3 Ongoing Procedure Performance Veri- fication involves monitoring the AP performance during use, which is a continuous exercise to con- firm the fitness of the AP. This stage helps to ensure that the AP remains in control during routine use and continues to meet the ATP criteria (28). Despite the existing ICH guidelines Q8–Q12 out- lining 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 ICH Q(R2) ICH Q14 Validation Expansion of the scope for other techniques Validation of multivariate procedures/models Knowledge Management vs Checkbox Exercise Real Time Release Tests Minimal vs Enhanced Approaches forProcedure Development Analytical Procedure Life Cycle Management Quality Risk Management Post-Approval Changes of Analytical Procedures Multivariate Analytical Procedures Analytical Procedure Life Cycle The Quality Target Product Profiles (QTPP) Analytical Procedure 1 Analytical Procedure 2 Analytical Procedure n The Analytical Target Profile (ATP) Stage 1 Stage 2 Stage 3 Procedure Design Procedure Performance Qualification Ongoing Procedure Performance Verification Continued Improvement Knowledge Management FIGURE 2. Analytical procedure life cycle framework described in USP <1220>. Reproduced from Reference (28).