In June and July we discussed Personnel Qualification and Environmental Monitoring Requirements for Compounded Sterile Preparations (CSPs) for Categories 1, 2, and 3. This month we will discuss Release Inspections and Testing for Categories 2 and 3.
Category 2:
- Must be prepared in a cleanroom suite
- May be assigned a BUD of >12 hours at controlled room temperature or >24 hours if refrigerated
Category 3:
- Have additional requirements that must be met at all times
- May be assigned a BUD longer than established for Category 2 CSPs, up to 180 days
Visual Inspection:
- This determines whether the physical appearance of the CSP is as expected (e.g. free of inappropriate visible particulates or other foreign matter, discoloration, or other defects).
- This confirms the CSP and its labeling match the prescription or medication order.
- This also includes visual inspection of container closure integrity (e.g. checking for leakage, cracks in the container, or improper seals).
Sterility Testing:
- This qualitative test is applied to substances, preparations, or articles required to be sterile. A satisfactory result indicates that no contaminating microorganism has been found in the sample examined under the conditions of the test.
- Method Suitability is required for USP <71> citation.
- An appropriate sample volume of a product lot is filtered or directly inoculated into two microbial growth medias.
- After an appropriate incubation period, the sample is observed for turbidity.
- After the sample has completed testing, a Certificate of Analysis (COA) is issued stating a Pass or Fail result.
Rapid Sterility Testing:
- If an alternative method is used for sterility testing, the method must be validated (see USP <1223>) and demonstrated to be suitable for that CSP formulation.
- Where USP <71> requires between 14 and 18 days of incubation before a final test result, a rapid sterility test result can be generated after only 6 days of incubation.
- This Celsis method can test all sample types including solutions, oil, and suspensions.
- Method Suitability is required.
- An appropriate sample volume of a product lot is filtered or directly inoculated into two microbial growth medias.
- After an appropriate incubation period, an analysis on the media is performed to detect microbial growth.
- After the sample has completed testing, a Certificate of Analysis (COA) is issued stating a Pass or Fail result.
Bacterial Endotoxin Testing:
- The USP <85> Bacterial Endotoxins Test (BET) is a quantitative test to detect or quantify endotoxins from Gram-negative bacteria using lysate derived from horseshoe crabs.
- With a kinetic turbidimetric method, a small amount of sample is prepared via serial dilution, along with any necessary additional reagents to overcome enhancement or inhibition effects.
- The prepared sample is transferred to a 96-well plate, and placed into a plate reader.
- Over the course of approximately an hour, the reader examines the wells for a reaction between the lysate and any endotoxin in the product samples.
- Based on either a lack of reaction, or the time taken to observe a reaction, the system calculates a quantitative result based on the sample preparation.
- At the completion of the test, a numerical value is given and reported on a Certificate of Analysis (COA).
- A comparison between the test result and the endotoxin limit for a sample determines whether the test is a Pass or Fail result.
Antimicrobial Effectiveness Testing:
- USP <51> Antimicrobial Effectiveness must be demonstrated for aqueous-based, multiple-dose topical, and oral dosage forms, and for other dosage forms such as ophthalmic, otic, nasal, irrigation, and dialysis fluids.
- In addition, whether inherent in the product or produced because of adding an antimicrobial preservative, antimicrobial effectiveness must be demonstrated for all injections packaged in multiple-dose containers or for other products containing antimicrobial preservatives.
- For this test, aqueous is defined as a water activity of more than 0.6.
- Method Suitability is required for USP <51> citation.
- Separate volumes of product sample are inoculated with high CFU counts of 5 different representative challenge organisms.
- Depending on which of the four categories in the chapter a product falls into, petri plates are prepared with growth media and a sample of the inoculated product at specific intervals over a 28-day period.
- At each of the plating intervals, a CFU count is obtained and compared against the criteria in the chapter.
- At the conclusion of the 28-day incubation and final plating, a Pass or Fail result is reported on a Certificate of Analysis (COA), depending on whether the product met the criteria in the chapter at each plating interval.