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Pharmaceutical Technology Regulatory Sourcebook October 2020 35 How many determinations? The methenamine man- delate monograph, like all other monographs, gives the requirement for a single determination, which is not usually best analytical practice. However, the General Notices, 7.10 clearly states, "Analytical re- sults observed in the laboratory (or calculated from experimental measurements) are compared with stated acceptance criteria to determine whether the article conforms to compendial requirements. The reportable value, which often is a summary value for several individual determinations, is compared with the acceptance criteria. The reportable value is the end result of a completed measurement pro- cedure, as documented" (11). In other words, the documented analytical pro- cedure must include the replication to be adopted and the method of calculating the reportable value must be explicitly defined. Monograph tests for methenamine mandelate. As seen in Figure 3, the tests in the monograph to be performed for methenamine mandelate are: • Identification by IR spectroscopy • Assay by titrimetry • Impurities by observation, gravimetry, and titrimetry • Water content by gravimetric analysis. The last three (assay, impurities, and water con- tent) are classical analytical chemistry tests, which are usually performed manually, with data col- lected and recorded on paper by observation. Figure 3 shows a range of analytical procedures that could be found in a pharmacopeia, from tests by observation to complex chromatographic or spectroscopic methods. It also highlights some of the main data integrity issues associated with the different analytical methods. Methods involv- ing USP <1058> Group C systems (18), typified by chromatographic and spectroscopic methods, are shown in green. If the application software has adequate technical controls (e.g., definition of user roles, audit trails, etc.) and it has been configured correctly to protect electronic records Figure 3. The spectrum of pharmacopeial analytical procedures includes some methods with greater data integrity risk. UV is ultraviolet; IR is infrared; LIMS is laboratory information management system; ELN is electronic lab notebook; LES is lab execution system. Revised fig 1 (colors added and some other changes) Revised fig 3 (only change is in bottom line text) United States Pharmacopoeia (USP) General Notices Monograph General Chapters < 1000 General Chapters >1000 Procedure implementation in an individual laboratory • USP <1058> Analytical Instrument Qualification • USP <1029> Good Documentation Practice Analytical Procedure for each Test • Reference Standards USP <11> • Reagents • Legal requirement • Tests for any sample taken over life (not batch) • Mandatory unless defined in Monograph or General Chapter • Mandatory • Key parameters and acceptance criteria • Informational (strong guidance) • Best practice approaches Classical Methods Observation Classical Methods Paper Records Classical Methods Some hybrid records but primarily paper Instrumental Methods Hybrid: electronic records with printouts Instrumental Methods E- working enforced by technical controls Spectrum of Pharmacopoeial Test Methods Greater data integrity risk through lack of objective evidence Procedural control can be inconsistent Technical controls lower data integrity risk Consistent operation Colour Odour Appearance Titration Analytical Balances pH Meters Loss on Drying Chrom Data Systems UV, IR systems Chrom Data Systems LIMS, ELN or LES interfaced to instruments