| 470 | | 10. ESTABLISHING BEYOND-USE DATES |
| 471 | | Each CNSP label must state the date beyond which the preparation cannot |
| 472 | | be used and must be discarded (i.e., the BUD). The parameters described in |
| 473 | | this section must be considered before establishing these dates. |
| |
| +Suggest inserting the word "appropriately" prior to "discarded." |
| |
| 474 | | 10.1 Terminology |
| |
| 501 | | 10.2 Parameters to Consider in Establishing a BUD |
| |
| 520 | | strong>10.3 Establishing a BUD for a CNSP |
| 521 | | The BUDs indicate the days after the CNSP is prepared and beyond which |
| 522 | | the CNSP cannot be used. The day that the preparation is compounded is |
| 523 | | considered Day 1. |
| |
| +The day on which the preparation is compounded should be Day 0 (zero), not Day 1. With short BUDs, the loss of a day can be important. A theoretical 1-day BUD would be 24 hours after it was compounded; 2 days 48 hours; 3 days 72 hours, etc. |
| |
| 524 | | If there is a USP�NF compounded preparation monograph for the CNSP, |
| 525 | | the BUD specified in the monograph must be used, unless a shorter BUD is |
| 526 | | required as described below. If there is no USP�NF compounded preparation |
| 527 | | monograph for the CNSP, Table 3 represents the maximum BUDs for CNSPs |
| 528 | | that are packaged in tight, light-resistant containers unless there is a CNSP |
| 529 | | specific stability study as described below. The BUDs in Table 3 are based on |
| 530 | | the ability of the CNSP to maintain chemical and physical stability and to |
| 531 | | suppress microbial growth. APIs or ingredients known to be susceptible to |
| 532 | | decomposition will require shorter BUDs (see 10.3 Establishing a BUD for a |
| 533 | | CNSP, Shorter Buds May Be Required). |
| |
| 534 | | Table 3. Maximum BUD by Type of Preparation in the Absence of A |
| 535 | | CNSP-Specific Stability Information |
| |
| +Comments on Table 3: |
| |
| +30 days for preserved aqueous dosage forms is good. |
| |
| +The reduction for nonaqueous dosage forms from 180 days to 90 days is very problematic, and I'm not sure that there is any justification for this. It should remain at 180 days. Also, USP Chapter <1112> states that "Nonaqueous liquids or dry solid dosage forms will not support spore germination or microbial growth due to their low water activity." Again, what basis was used to drop from 180 days to 90 days for nonaqueous dosage forms? |
| |
| 557 | | The BUDs specified in Table 3 for aqueous dosage forms and nonaqueous |
| 558 | | dosage forms may be extended up to a maximum of 180 days if there is a |
| 559 | | stability study (published or unpublished) using a stability-indicating assay |
| 560 | | for the specific API, CNSP, and container�closure that will be used. |
| |
| +Allowance should be made if the compounded preparation is being used in a clinical study and can be assayed periodically to extend the BUD past 180 days. Some studies may go on for a year or two, and it is preferable to use the same lot of drug product throughout the study. |
| |
| 561 | | If the BUD of the CNSP is extended beyond the BUDs in Table 3, an |
| 562 | | aqueous CNSP must first be tested for antimicrobial effectiveness (see |
| 563 | | Antimicrobial Effectiveness Testing <51>) at the end of the proposed BUD |
| 564 | | unless such testing was done as part of the referenced stability study. The |
| 565 | | test must be conducted once for a particular CNSP. If changes are made to |
| 566 | | the ingredients or storage conditions of the CNSP, the test must be |
| 567 | | conducted for the new preparation. When a range of API concentrations are |
| 568 | | compounded in the same CNSP formulation and stored under the same |
| 569 | | conditions, the antimicrobial effectiveness test can be conducted for the |
| 570 | | highest and lowest concentrations, and the results can be similarly |
| 571 | | extrapolated for the concentrations within the range studied (e.g., bracketed |
| 572 | | study design). |
| |
| +Just to be clear, if there are published studies using stability-indicating analytical methods that provide a BUD for a preserved aqueous dosage form that shows the API is stable for 90 days, then the Antimicrobial Effectiveness Testing <51> must be done before using that 90-day date? If there has been NO reported instance of microbial growth in compounded oral preparations using commercial preserved vehicles, this does not seem necessary. Commercial oral liquid vehicles contain preservatives and have already been tested. Why address a problem that does not seem to exist? |
| |
| 572 | | SHORTER BUDS MAY BE REQUIRED |
