Mark G. Klang, MS, RPh, BCNSP, PhD
Core Manager, Research Pharmacy
Memorial Sloan Kettering Cancer Center
New York, New York
The newly revised United States Pharmacopeia (USP) Chapter <797> calls for a beyond-use date of 42 days.1 This guidance does not make allowance for the period of time needed to conduct a valid sterility assessment. This ruling is misguided, as it will motivate compounders to conduct in-house testing to reduce transportation time and skip appropriate validation tests in an effort for expedited results. The U.S. Food and Drug Administration (FDA) draft guidance for 503a pharmacy states2:
The compounder holds for distribution no more than a 30-day supply of a particular 325 compounded drug product.
The FDA document defines distribution as2:
For distribution means drug product that is available for immediate distribution and does not include drug product that is being held pending receipt of the results of release testing such as sterility testing.
A standard USP Chapter <71> test requires 14 days for results. It would appear that both the USP and the FDA have similar goals of a month usage after a sterility test has been conducted. The current version of USP <797> allowed sterile products to be used up to their chemical stability once sterility tests have been verified.3
The new USP <797> version limits leeway after conducting a sterility test and will push facilities to expedite results to attain longer usage of the sterile products. There is a concern that there will be more internal testing to shorten times after testing.
A verifiable sterility test in accordance with USP Chapter <71> is fairly complex. To ensure the results of a sterility test are reflective of an actual lack of contamination, it is necessary to initially and periodically conduct a Bacteriostasis and Fungistasis (B&F; also known as Method Suitability validation) analysis. Although the requirement is not specifically mentioned in USP <71>, many labs (e.g., Alcami, Analytical Research Labs, Gibraltar, Lancaster) require three times the largest amount of sample you plan to have tested, based on batch size. This is necessary to determine if the dilutions used for analysis can support growth of aerobic, anaerobic, or fungal contamination. USP denotes the term Method Suitability to identify the steps to determine if the preparation to be tested will interfere with the assay.
USP Chapter <71> delineates the quantities to be tested based on batch size. For batches under 100 units, 10% will be selected at random, while batches greater than 100 units, 2% will be selected at random. See Table 3 from USP 39-National Formulary 34 Chapter <71>.
Table 3. Minimum Number of Articles to be Tested in Relation to the Number of articles in the Batch.
|Number of Items in the Batch*||Minimum Number of Items to be Tested for Each Medium (Unless Otherwise Justified and Authorized)**|
|Not more than 100 containers||10% or 4 containers, whichever is the greater|
|More than 100 but not more than 500 containers||10 containers|
|More than 500 containers||2% or 20 containers, whichever is less|
|◆ For large-volume parenterals||2% or 10 containers, whichever is less|
|Pharmacy bulk packages (<5 g)||20 containers|
|Pharmacy bulk packages (≥5 g)||6 containers|
|Bulks and blends||See Bulk Solid Products◆ |
|Ophthalmic and Other Noninjectable Preparations|
|Not more than 200 containers||5% or 2 containers, whichever is the greater|
|More than 200 containers||10 containers|
|If the product is presented in the form of single-dose containers, apply the scheme shown above for preparations for parenteral use.||
|Catgut and other surgical sutures for veterinary use||2% or 5 packages, whichever is the greater, up to a maximum total of 20 packages|
|◆ Not more than 100 articles||10% or 4 articles, whichever is greater|
|More than 100, but not more than 500 articles||10 articles|
|More than 500 articles||2% or 20 articles, whichever is less◆ |
|Bulk Solid Products|
|Up to 4 containers||Each container|
|More than 4 containers, but not more than 50 containers||20% or 4 containers, whichever is greater|
|More than 50 containers||2% or 10 containers, whichever is greater|
|*If the batch size is unknown, use the maximum number of items prescribed.|
|**If the contents of one container are enough to inoculate the two media, this column gives the number of containers needed for both the media together.|
Thus for a batch of 100 30-mL vials, 10 vials will be selected for testing for sterility. The B&F test requires 3 times the number of units. Although the B&F can be carried out simultaneously with the sterility tests, contract labs generally await results of B&F before attempting sterility tests. Each time the process changes, or the volume of units or the number of units, a new B&F is done to validate the new process.
The standard turnaround time for a 14-day USP <71> sterility test by membrane filtration is 20 days conducted by a contract laboratory. A B&F can be conducted in 10 to 14 days.
For each new sterile compounded batch prepared, the initial testing will take 34 to 40 days depending on the timing of the sample delivery to the contract laboratory. Adoption of the new USP <797> guidance will do a disservice to the process of obtaining a validated sterility test and force compounders into less secure processes for sterility assessment.
- United States Pharmacopeial Convention, Inc. General Chapter <797> Pharmaceutical Compounding—Sterile Preparations. [USP Website.] September 25, 2015. Available at: www.usp.org/usp-nf/notices/general-chapter-797-proposed-revision. Accessed June 20, 2016.
- U.S. Department of Health and Human Services. U.S. Food & Drug Administration. Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry 2016. [FDA Website.] Available at: www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/UCM496286.pdf. Accessed June 20, 2016.
- United States Pharmacopeial Convention Inc. General Chapter <797> Pharmaceutical Compounding—Sterile Preparations. Rockville, MD: U.S. Pharmacopeial Convention, Inc.; Current Edition.