Compounding Regulations: Are new validation approaches allowed for alternative sterility methods? (Part 2 of 2)

We’re frequently asked when to validate rapid methods using USP chapters <72> and <73> vs <1223>. Let’s work out the answers together  

Validation per <72> and <73> may be too good to be true.

USP <797> is the standard for Compounded Sterile Preparations for our 503A readers. This chapter highlights everything related to release testing. Let’s decipher what the chapter says for sterility testing.  

In the sterility testing section, the chapter says alternative methods are allowed, but they must be validated to be equivalent to the traditional sterility method per <1223>.  There is nothing in the compounding chapter that refers to:

• Risk based release
• Short-life products
• <72>, <73>, or <1071>  

Likewise, FDA’s guidance for 503B facilities talks a good deal about sterility testing.  This guidance specifically points to USP <1223> for methods to validate a sterility test alternative to USP <71>.  Like <797>, it makes no mention of short-life products or risk-based release.

Chapters <72> and <73> describe how to apply chapter <1071> using CO2 or ATP-based methods. Per chapter <1071>’s title, the chapter applies to products intended to be sterile.  However, the tests are not referred to as sterility tests.  They are rapid microbial tests for short-life products, which are not the same as the sterility standard that compounded products/preparations must meet.  

The rapid microbial test chapters allow for a higher limit of detection (LOD) than true sterility testing.  While this higher LOD allows a trade-off of faster time for results – assuming the site has the appropriate risk justification to use a less sensitive test based on product administration needs and manufacturing controls – the validation does not confirm equivalence to the traditional sterility test method like the methods in <1223> do.  As mentioned earlier, this is not acceptable per <797>, nor is it noted as an acceptable strategy in FDA guidance for 503Bs.

<72> and <73> are explicitly for short-life products.  They provide some ways to control the sensitivity of the test to make it close to equivalent to the traditional method.  They require method suitability to have a lower spike inoculum and a new determination of incubation period test.  However, they do not confirm equivalency to the traditional method at the target 1 CFU limit of detection.  

But, But, But!  You said…!

So, what about those bold points from the previous post?  Don’t they supersede what’s written in <1223>? Let’s look at those in a new light:

Listed Example: Yes, compounders are a manufacturing example where chapters <72> and <73> could apply.  However, that’s because compounders could in theory make some products that fall into the chapters’ definition of short life. Typical compounded preparations or products don’t actually fit this definition  

“Wait, what about the...”

Short BUDs: Yes, short buds impact the shelf life of the product.  However, the new chapters are intended for products that must be administered prior to when a result can be available with the traditional 14-day sterility test, such as many novel cell and gene therapy products whose manufacturing falls outside the definition of compounding.  Compounders that perform sterility testing actually extend the products’ shelf life. Those products are available for months after compounding, and do not fit the <72>, <73>, and <1071> definition of short life.

Rapid Method Technology: Yes, it’s still easy to imagine a regulatory inspector coming to your site, seeing your CO2 or ATP-based method, and asking to see your validation per <72> or <73>.  However, these chapters are new to everyone, including SMEs like the authors, compounders, and regulators.  We wrote this piece to explain our understanding of these chapters and to bring awareness to the discrepancies we discussed.  When an inspector comes on site, we hope this piece provides you with enough information to discuss the intentions of all the chapters addressed here.  

So, let’s be positive

For routine use, this may seem like a disappointing conclusion.  However, it’s worth noting a few benefits of validating using the <1223> approach.

History of Acceptance: Chapter <1223> provides a well-understood approach for validating alternative methods.  Manufacturers of FDA- approved drugs like Baxter and Roche, large 503B compounders like Fagron Sterile Services, and Contract Testing laboratories that cater to compounders, like ARL and Pharmetric, have a history of validating their rapid methods per <1223> and having those validations successfully reviewed by inspectors.  

Method Suitability Simplicity: Method suitability, as outlined in USP Sterility testing chapter <71>, requires an inoculum of <100 CFU. USP <72> and <73> require method suitability to be performed with <10 CFU.  This inoculum is difficult to obtain routinely.  You may find after incubation that your inoculum was higher than 10. We’ve worked with multiple sites that have expressed frustration with this practice. They need to open deviations for each inoculum that did not meet requirements! If you have a large or growing product portfolio, this frustration may get you, too.  

The validation process is ultimately a decision that belongs to your site, but we hope this information can help you understand the roles of these various chapters and allow you to make the best decision based on your process, products, and release needs. 

This is the second and final installment in this series about validating rapid microbial tests in the compounding pharmacy arena. Check out the entire series here.