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Pharmaceutical Technology Regulatory Sourcebook October 2020 39 chapters in addition to USP <731> (16), namely USP <41> (23) and USP <1251> (24). From these inputs, an analytical procedure process f low for LOD can now be developed and is shown on the right-hand side of Figure 5. There is also a specific direct input from USP <1029> (14) into the proce- dure for second person review, which is consistent with the requirement in 21 CFR 211.194(a)(8) (15). The detailed interpreted analytical procedure is shown in Figure 5. On the left-hand side of Figure 5 are the same steps from Figure 4, now broken down into 25 individual process steps with associated ac- tions and calculations (see Figure 6 for details) to generate the analytical record for review. In this example, the laboratory has chosen to make the test in duplicate. Apply ALCOA+ requirements To illustrate an approach to applying the ALCOA+ requirements to pharmacopeial testing, consider a LOD analysis for betamethasone valerate inter- preted in Figure 4 and Figure 5. Figure 6 contains a detailed description of the 25 analytical process steps involved in a LOD analysis according to USP <731> (16); the next column lists the docu- mentary evidence produced at each step, and the nine columns to the right list the nine ALCOA+ requirements. If a criterion applies at a test step, then a tick is placed in the appropriate column. The following assumptions are made in Figure 6: • Complete is only recorded at end of the anal- ysis, as it is the responsibility of both the per- former and reviewer to ensure completeness. Figure 6. Application of ALCOA+ requirements to a United States Pharmacopeia (USP) <731> Loss on Drying analysis. ALCOA is attributable (A), legible (L), contemporaneous (C), original (O), and accurate (A), and ALCOA+ adds complete (C), consistent (C), enduring (E), and available (A). Step # Analytical Procedure Description Documented evidence A L C O A C C E A 1 Interpreted procedure of USP monograph test requirement Authorised analytical procedure ü ü ü ü ü ü 2 Obtain uniquely number approved blank worksheet from the Quality function Traceable paper record issued ü ü ü ü 3 Analyst 1 adds the batch specific information and identity Record on the worksheet ü ü ü ü 4 Identify balance and oven to be used Record on the worksheet ü ü ü ü 5 Check balance calibration and oven information Record on the worksheet ü ü ü ü 6 Tare balance and weigh two dried glass weighing bottles with stoppers and print values Attach and initial the annotated balance print out to the work sheet ü ü ü ü 7 Dispense two sample amounts of between 1.5 to 2.0 g into the dried glass weighing bottles ü ü ü 8 Tare balance and re weigh the two dried glass weighing bottles and print values ü ü ü 9 Calculate the accurate weight of the samples and compare with the acceptance criterion Calculation record on worksheet ü ü ü ü 10 Record the oven temperature before placing the weighing bottles and stoppers in to it Record on the worksheet ü ü ü ü ü 11 Record time weighing bottles and stoppers placed into the oven Record on the worksheet ü ü ü ü ü 12 After 3 hours record, the oven temperature and the time Record on the worksheet ü ü ü ü ü 13 Remove weighing bottles from the oven and place into a desiccator to cool recording the time Record the time on the worksheet ü ü ü ü ü 14 Are both before and after oven temperatures in the range 105±2°C? If so initial acceptance ü ü ü 15 Calculate the drying time in the oven (must be greater than or equal to 180 minutes) Calculation record on worksheet ü ü ü 16 Record the time taken out of the dessicator Record the time taken out of the dessicator on the worksheet ü ü ü ü 17 Calculate the cooling time. The time in the desiccator must be at least 45 minutes Calculation record on worksheet ü ü ü ü ü 18 Tare balance and reweigh the two stoppered glass weighing bottles containing the samples and print values Attach and initial the annotated balance print out to the work sheet ü ü ü ü 19 Calculate the loss in weight for each sample and calculate the % LOD for each sample to 3 significant figures Calculation record on worksheet ü ü ü ü ü 20 Calculate the difference beween the two individual results Calculation record on worksheet ü ü ü ü ü 21 Compare with the defined acceptance criterion Initial acceptance or not ü ü ü 22 If acceptable, calculate the mean value which is then rounded to the number of significant figures in the standard as the reportable result Calculation record on worksheet ü ü ü ü ü 23 Compare the reportable result is in accordance with the Pharmacopeial standard Record decision and initial ü ü ü ü ü 24 Conduct a full second person (Analyst 2) review in accordance with the standard procedure Record review decision and initial ü ü ü ü ü 25 Return the uniquely number completed and reviewed worksheet to the Quality function Traceable paper record returned and reconciled ü ü Attach and initial the annotated balance print out to the work sheet üü