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24 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com TABLE I. Comparison of terminology and elements between International Council for Harmonisation (ICH) Q14 and United States Pharmacopeia (USP) General Chapter <1220>–ATP and Stage 1. Stages of APLC (<1220>) APLC Elements ICH Q14 USP GC <1220> ATP ATP Concept: "It consists of a description of the intended purpose, appropriate details on the product attributes to be measured and relevant performance characteristics with associated performance criteria." "The ATP includes the performance requirements for a single attribute or a set of quality attributes." Note: It does not mention the role of measurement uncertainty (MU) and total analytical error (TAE) except in Annex A where TAE is included in the example of ATP. Same concept: "The ATP is a prospective description of the desired performance of an analytical procedure that is used to measure a quality attribute, and it defines the required quality of the reportable value produced by the procedure, aligned with the quality target product profile (QTPP)." It emphasizes the importance of establishing suitable performance requirements (e.g., maximum MU and maximum acceptable total error for quantitative procedures). Stage 1 Proven Acceptable Ranges (PAR) "A characterized range of an analytical procedure parameter for which operation within this range, while keeping other parameters constant, will result in an analytical measurement meeting relevant performance criteria. Univariate examination of a single parameter can establish PARs for the analytical procedure." Concept is not described. Stage 1 MODR Concept: "It consists of combined ranges for two or more variables within which the analytical procedure is shown to be fit for the intended use." Movements within range: "Moving within an established parameter (e.g., PAR or MODR) range does not require regulatory notification. "If appropriately justified and validated a PAR or MODR allows flexibility within the approved range(s) to be managed within a company's PQS. Changes outside of the approved ranges or expansion of said ranges require regulatory reporting." "For practical reasons and following a risk-based approach, it may not be necessary or possible to validate the entirety of a MODR. The part of a PAR or a MODR intended for routine use in the 210 analytical procedure must be covered by validation data." Note: It shows two options for MODR validation, but it does not emphasize the importance of robustness study to generate the MODR. It does not cover a comprehensive validation protocol for MODR. Same concept: Concept: "The MODR is the multivariate space of analytical procedure parameters that ensure the ATP is fulfilled and therefore provide assurance of the quality of the measured value. The MODR should ideally be obtained through well-designed experiments that consider multivariate interactions." Knowledge about robustness "also enables the determination of robust operation regions for procedure parameters and, if desired, a method operable design region (MODR)". Movements within the range: "An adjustment to a procedure parameter to a value within the range that was previously qualified (e.g., a change within the MODR) may not require additional experimentation before implementation. However, any changes to the routine operating conditions within the MODR should be risk assessed against the ability to meet the ATP criteria and further studies performed as needed prior to implementation of the new operating conditions." Note: It does not provide guidance on how to validate the MODR. Stage 1 Replication Strategy Mentioned only in Annex A. It does not provide comprehensive guidance. Replication Strategy is considered as one of the elements of stage 1. Stage 1 Analytical Control Strategy "Analytical Procedure Control Strategy (APCS): should ensure that the analytical procedure performs as expected during routine use throughout its lifecycle and consists of a set of controls, derived from current understanding of the analytical procedure including development data, risk assessment and robustness." "It should be defined before validation (ICH Q2) and should be confirmed after validation has been finalized." Different term: Analytical Control Strategy (ACS) Same concept: "The ACS is a set of controls needed to ensure the procedure performs as expected and plays a key role in ensuring that the ATP is realized throughout the life cycle. The preliminary ACS is identified during the procedure development process in Stage 1 and includes System Suitability and other environmental or procedure controls needed for the procedure to meet the ATP." Stage 1 Established Conditions (EC) "ECs could consist of performance criteria and the analytical procedure principle (i.e., the physicochemical basis or specific technology), and set points and/or ranges for one or more parameters (in line with ICH Q12). ECs can be identified using risk assessment tools prior knowledge, and learnings from uni- and/or multi-variate experimentation." The term EC is not considered in GC 1220, where the final conditions and the validated operating range (portions of the MODR) along with risk criteria and the set of controls can be considered equivalent to EC. Validation