Life cycle of analytical Methods-NEW PHASE IN PHARMACEURICAL /Healthcare industry Uncontrolled variation is the enemy of quality All analytical measurements are wrong; it’s just a matter of how large the errors are, and whether they are acceptable.

Outline » Background and Brief on Lifecycle Approach » CFR & FDA view »QbD and CMA state in control and Roadmap » Summary & Approach » TMU ( Target Measurement Uncertainty) » QbD key components ICH Q8 General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle An analytical procedure must be shown to be fit for its intended purpose. It is useful to consider the entire lifecycle of an analytical procedure when approaching development of the procedure, i.e. its design, development, qualification, and continued verification. The current concepts of validation, verification, and transfer of procedures address portions of the lifecycle but do not consider them holistically. "Trend analysis on method performance should be performed at regular intervals to evaluate the need to optimize the analytical procedure or to revalidate all or a part of the analytical procedure. "The Analytical Procedure Lifecycle" for integration into USP. Furthermore, also in the non-regulated environment a growing interest on life cycle management is seen. Quality-by-design based method development results in increased method robustness. Thereby a decreased effort is needed for method performance verification, and post-approval changes as well as minimized risk of method related out-of-specification results. This strongly contributes to reduced costs of the method during its life cycle.

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle Assure that the Method remains in a State of Control

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle » Required Quality of Reported value from Analytical Method used . » Derived from external requirements (Consideration of TMU) » Acceptable level of risk of making an incorrect decision is considered when design the ATP. » Reported value can be Mean of Multiple analytical Results if replication strategy in place or documented. » For Good ATP Selection :Sample to be tested ,Matrix in which the analyte will be present, Allowable error predicted from Accuracy and Precision The current ICH and USP validation guidance can be incorporated into an ATP, with emphasis on the quality of the reportable value as shown for a drug product assay.

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle Examples for ATP # 1 The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] with the following requirements for the reportable values: Accuracy = 100% ± D% and Precision ≤ E%. X,Y,Z –May be impurities or ingredients ,Value for D and E should be specified i.e. D can be % of label claim and E may be in RSD %. Alternative units can be used but its should not be UNAMBIGUOUS. Examples for ATP # 2 The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] so that the reportable values fall within a TMU of ±C%.

The purpose of offering an General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle The purpose of offering an alternative approach to the classical analytical validation and subsequent verification and transfer, viewing these activities as a continuum and closely interrelated rather than as discrete actions. This enhanced approach potentially offers several advantages, including: • Improved understanding of the procedure and control of sources of variability, which are linked to the intended use of the procedure as described in the analytical target profile (ATP) • Procedures that are more robust, resulting in fewer failures during use and during qualification in a new laboratory • Reduction of overall resources required for a new or revised procedure. The levels of effort, formality, and documentation should be commensurate with the level of risk • Identification of adverse trends, allowing proactive measures and facilitation of continued improvements and change control through continued monitoring

Quality of Reported Analytical Value TMU Quality of Reported Analytical Value Maximum uncertainty with a reportable results-While still remains fit for its intended purpose Measurement uncertainty (MU) allows the risk and probability to be quantified and applied to the use of the data. If you don’t know where you are going, any road will do. MU is a major part of defining “where you are going”. Measurement Uncertainty is “a parameter associated with the result of a measurement that characterizes the dispersion of the values that could reasonably be attributed to the measured” General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle Decision Rule A documented rule ... that describes how measurement uncertainty will be allocated with regard to accepting or rejecting a product according to its specification and the result of a measurement.

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

General Chapter Prospectus: <1220> The Analytical Procedure Lifecycle

Quality-by-design procedures for products as mentioned in ICH guideline Q8 and transfer to analytical quality-by-design.