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20 Pharmaceutical Technology LABORATORY BEST PRACTICES 2018 P h a r mTe c h . c o m Analytical Methods well as column manufacturers, should be carefully evaluated. These evaluations coupled with his- torical knowledge and information gleaned from comprehensive literature searches help to identify critical method parameters (CMP). At this stage, a risk analysis should be conducted to identify and rank parameters that are likely to impact method performance and, therefore, con- formance to the ATP. Risk assessments are typi- cally iterative throughout the lifecycle of a method. They are performed during method development to identify method parameters that present highest risk as well as the end of method development to ensure that any potential risks associated with the developed method are identified, as appropriately, and mitigated. Risk analysis is also performed prior to method transfer or during a product change (e.g., route of administration, formulation, or process). The risk assessment performed during method development should be focused on identifying fac- tors that could impact method linearity, precision, accuracy, signal-to-noise, and specificity, in addi- tion to other method parameters. The risk analysis should include materials needed for method execu- tion, equipment, operators, and various method elements. Using chromatography as an example, such elements would likely include column selec- tion, column temperature, mobile phases, run time, f low rate, and gradient. Each of these risk-analy- sis components are assigned a risk weight; those deemed to have medium-to-high risk would require a mitigation plan. The mitigation plan is typically comprised of non-experimental fixes for materials, operators, etc., and experimental fixes for method elements (i.e., column temperature, gradient, flow rate) that are addressed through a DoE approach. Further risk assessment will also be performed when transitioning the method from development to the commercial stage. For this assessment, focus is placed on method ruggedness or more specifi- cally on the sources of reagents, laboratory prac- tices, the environment, testing cycle times, and equipment availability. Design of experiment Once a n appropr iate r isk a na lysis has been completed, it is time to design the experiments. For t his, one shou ld consider t he fol low i ng steps: • Be mindful of the method requirements per ATP such as repeatability, precision, accuracy, limit of detection (LOD)/limit of quantitation (LOQ), linearity, and resolution. • Define the range of concentrations to be mea- sured by the method, along with solution matrix of the analyte. • Obtain/prepare reference standards for bias/ac- curacy evaluation. • Define discrete steps in the method, previously identified in early scouting studies. • Identify responses that address method purpose. • Identify an error control plan. • Design the experimental matrix and sampling plan. • Run study. • Analyze results and determine settings and pro- cessing conditions that result in desired preci- sion, accuracy, and linearity. • Document design space of the method and upper and lower limits for critical parameters. • Run confirmatory study for method settings/ limits.