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40 Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2021 P h a r mTe c h . c o m Best Practices: Part 2 Calculation protocol (Phase 3) The final phase is where the metadata and measurement data are combined to produce the reportable value if mea- surement and individual result ranges are within the capa- bility acceptance criteria of the procedure itself. Rounding instructions should be specified or referenced. A typical scheme is shown in Figure 5. Calculation protocols need to explicitly state the calcu- lations and equations to be used in determining procedure capability and compliance with predefined acceptance criteria, as well as those to be used for the calculation of individual results and their combination to generate a re- portable value. The calculation protocol must include the reference standards and related measurement equations in a similar manner to those of the portion preparations when calculating the individual results. Reportable result versus reportable value. The term 'result' is given to individual calculations from the metrological data relating to a specific test portion. The term 'value' is reserved for the combination of individual results. This nomenclature should be defined as the United States Phar- macopeia uses both these terms interchangeably. Analytical record All data and metadata generated as part of Phase 2, Ana- lytical Operations; and Phase 3, Calculation protocol for a given analytical sample should be included together with the appropriate compliance requirements under GMPs. Second-person review should ensure traceability and compliance throughout these phases. Summary An overall process f low covering the four Phases (0–3)— sampling plan, sampling process, analytical operations, and calculation protocol—has been proposed. The im- portance of the sampling and analytical records has been emphasized to ensure compliance and traceability as well as adherence to ALCOA+ —attributable, legible, contem- poraneous, original, and accurate, complete, consistent, enduring, and available—principles. Discussion of the final step of comparison of the report- able value with the specification has not been addressed in this paper as the investigation of out-of-specification results is well documented elsewhere. The author would welcome comments on the desirability, us- ability, and/or correctness of this approach particularly for reg- ulators, and quality control or quality assurance professionals. Acknowledgements The author wishes to thank Lucy Botros, Bob McDowall, Margarita Sabater, and Jane Weitzel for helpful comments and suggestions during the preparation of this paper. References 1. C. Burgess, Pharm Tech, Regulatory Sourcebook (September 2021). 2. K. H. Ebsbensen, Introduction to the Theory of Sampling (IMPubli- cationsOpen, 2020). 3. J. W. Merks, Sampling and Weighing of Bulk Solids (Tran Tech Publications, 1985). 4. F. F. Pitard, Pierre Gy's Sampling Theory and Sampling Practice (CRC Press, 2nd Edition, 1993). 5. Eurachem /CITAC, Measurement Uncertainty Arising from Sam- pling: A Guide to Methods & Approaches, 2nd edition 2019 6. ISO, ISO/IEC 17025, General Requirements for the Competence of Testing and Calibration Laboratories, 3rd edition (2017). 7. C. Burgess, Valid Analytical Methods and Procedures (Royal Soci- ety of Chemistry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igure 5. Example process flow for a typical high-performance liquid chromatography calculation protocol.