The USP published its second proposed revision to <797> Pharmaceutical Compounding — Sterile Preparations. Significant input from stakeholders was received after the original revision a few years ago, including over 8,000 written documents. The result is a document that looks much different than the original proposal. Here is a high level view of changes with a microbiological impact from the original method last revised in 2008.
There are now two categories of Compounded Sterile Product (CSP) versus the original three of Low, Medium and High Risk. The two categories (Category 1 and Category 2) are based on the compounding conditions, the probability of microbial growth, and the time period in which they can be used. Basically, if you are assigning a Beyond Use Date (BUD) of >12 hours at Controlled Room Temperature (CRT) or >24 hours at refrigerated temperature, you are Category 2. Additional testing and validation are required.
Environmental Monitoring (EM):
Disappointingly in my view, the minimum requirement for air sampling, viable and non viable, regardless of category, is still every six months. Two single snap shots over a year’s time will not give an accurate picture of the microflora in your facility or nor are two points a trend that will expose how well your gowning, disinfecting, engineering, and other processes are under control. See our piece about EM Investigations . Most of our compounding customers sample more frequently than twice a year.
Surface samples have increased to at least monthly. Unfortunately the Action Levels for Surface Samples in ISO 5 areas remain >3 cfu per contact plate. 3 colonies on a 25 cm square sterile surface where sterile compounding occurs is 3 more than what should be considered sterile.
Air levels have rightfully decreased, to <1 cfu/cubic meter in an ISO 5 PEC.
The confusing language from the current chapter has been clarified to state that plates which exceed action level should be identified to genus with the assistance of a microbiologist. FOCUS microbiologists perform microbial identifications by either genetic or biochemical profiling, always resulting in at least a genus ID.
Recommends a single media and the following incubation times for air and surface sampling: Tryptic Soy Agar (TSA) at 30 – 35C for 48 to 72 hours, then transferred to 20 – 25C for 5 – 7 days. This is a change from the previous suggestion of of Malt Extract Agar. There are advantages and disadvantages to this approach. An advantage is saving on the cost of a specialized fungal media. A disadvantage is the enhanced ability of MEA to actually culture wild mold versus TSA (we have data demonstrating this), and a lengthened incubation period before you can react to Action Levels.
There is a much enhanced section on how to select and use antimicrobial agents for the pharmacy. And for the first time, there is direct mention of sporicidal agents that have been shown to effective against Bacillus species, to be used at least monthly. See our piece about disinfectant efficacy
New detail is present on demonstrating that terminally sterilized CSP’s use a process to achieve a Sterility Assurance Level (SAL) of 10-6. Validation of cycles is required, utilizing Biological Indicators including Geobacillus stearothermoophilus for steam sterilization and Bacillus atrophaeus for dry heat sterilization.
Many pharmacies utilize depyrogenation ovens to remove potential endotoxin contamination from vials and other compounding equipment. The proposed chapter requires that the effectiveness be established and verified annually with endotoxin challenge vials, that result in a 3 log reduction of endotoxin.
All Category 2 CSP’s which have been assigned a BUD must have a sterility test performed — according to USP <71> or a validated alternative method. There has been a lot of confusion regarding Rapid Microbial Methods (RMM) for compounded product release, with some regulators stating that anything other than USP <71> is unacceptable under any conditions. It is encouraging to see science win out in this proposed revision.
Bacterial Endotoxin Tests are also required for all Category 2 CSPs assigned a BUD.
Preservative Efficacy Testing
If a compounded multi dose container is designed to contain more than one dose, and will be entered mulitple times, it should contain a preservative. The proposed revisions require multi-dose preparations be tested by USP <51> Antimicrobial Effectiveness Tests.
We hope this high level review of proposed changes that may impact your microbiological testing needs has been helpful. It is wonderful that the USP has listened to its stake holders. We have one more chance to get our comments in. Click here for more detail. November 30, 2018 public comment period will close.
Meanwhile, please contact us if we can help in anyway. All of us are FOCUSed on the same goal — patient safety.