Building the House of Rapid Sterility – A Successful Platform Approach to introducing Rapid Methods

Are you looking to get FDA approval for an alternative method? Large manufacturers have gone through the process and are willing to share their success story with you!?

Co-presenting the recent webinar “Building the House of Rapid Sterility – A Successful Platform Approach to introducing Rapid Methods,” with Sophie Drinkwater, Senior Scientist in Microbiology at AstraZeneca, was a great experience for me. Sophie outlined a strategic approach to bringing in an alternative sterility method that reduced the post-approval change burden and reduce validation time. I was able to provide some background on the flexibility of Celsis? technology for rapid sterility testing.?

The webinar ended with an abundance of audience participation with the question-and-answer period. The questions overflowed the allotted time, necessitating this follow-up to ensure everyone gets a thoughtful response. Inquiries related to Celsis process flow, applications, and flexibility with different product types were answered in this FAQ document. Here, I want to provide more background on the validation and regulatory acceptance of alternative methods, specifically with Celsis users.?

Let’s start with the general questions were received on validating Celsis and Charles River support. These questions touched on that subject:?

• How do you validate the rapid sterility test method??

• Are the volumes of 2.6.1. used for the rapid method??

• Does Charles River support the method transfer of the primary validation carried out at the vendor's site??

• Does method suitability need to be performed at each new site? If it has been demonstrated for the PSQ had been successfully done at another site??

Method validation consists of a lot of factors. When we’re discussing laboratory work needed for alternative sterility methods, most of what is needed is described in USP chapter <1223> and European Pharmacopeia chapter 5.1.6. These chapters are distinct from the compendial sterility chapters of USP <71> and European Pharmacopeia chapter 2.6.1. However, the test volume needed for a batch will be decided based on the recommendations of <71> and 2.6.1.??

In practice, users need to show they can detect down to 1 CFU at a rate that is not inferior to the traditional method. This testing should include the standard organisms used for bacteriostasis/fungistasis testing, but should also include organisms that are slow growing, stressed, or otherwise representative of the site’s past EM results. That is the short answer for evaluating rapid method Limit of Detection (LOD), Equivalency, and Specificity.?

Charles River can function as a contract laboratory that performs these tests for Celsis users. It is expected that each user performs method suitability on each new product they plan to test using Celsis. Each network must determine what their approach is to repeating method suitability for the same product at different sites. It would likely be a similar approach to current method transfer testing performed using the traditional method.??

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The audience understood that validation efforts don’t guarantee regulatory approval. They wanted to understand regulatory agencies’ attitude towards alternative methods. Here are the questions and direct responses related to that topic.?

Does CRL have a Master File with FDA CBER??

Ruggedness and Robustness data for Celsis AMPiScreen? sterility application is filed with the FDA. Similar data for Celsis Adapt? has been generated but is not filed. What we’ve found is agencies expect this data to be presented during review for each individual user’s application, and Charles River provides this data to customers. With that process, there isn’t much immediate benefit for Charles River to go through that filing process.?

How far off are we from getting the rapid method to be accepted by the regulatory authorities such as FDA and EU? Any guesstimate??

Celsis has already gained regulatory approval for routine use with all major regulatory agencies globally. These approvals have been in post-approval changes and new drug applications (or equivalent depending on the region).?

With the usual practice for creation of new USP chapters, it looks like certain alternative method technologies could be accepted without alternative method validation for short shelf-life products within a year. However, some inspectors from the FDA have made clear they are beholden to the Code of Federal Regulation, not the USP. They may still require alternative method validation. I can’t make a guesstimate that would be of any useful value to anyone reading this.?

Beyond the scope of just short shelf-life products, the European Directorate for the Quality of Medicines (EDQM) is exploring a certification scheme for rapid methods, whereby sponsors would submit a data package to EDQM for peer review. If package is considered sufficient, the method would be certified, and the end user could utilize the method as an EDQM certified method in that territory and potentially the observer countries. Should the certification proposal be approved, we expect Celsis will be certified by EDQM in the next 3 years.??

We are also working with other regulatory agencies globally to share our comprehensive data set in the hope of increased recognition of the appropriateness of this test for routine sterility release testing.??

Have any cell and gene therapy companies successfully validated and received FDA approval to use ATP-bioluminescence for release testing for a product containing high concentrations of CART-T cells??

There are no users of Celsis Adapt that have approval for routine use at this time. However, there are a few points to note:?

The Celsis Adapt instrument for cell and gene therapies is relatively new. It was released for commercial use in late 2021. The validation testing and filing process also takes a long time. There are customers with whom Charles River has completed laboratory validation work. They are currently going through the regulatory approval process.?

The validation approach with Celsis AMPiScreen sterility application and Celsis Adapt are nearly identical. The approach is also similar to the laboratory testing AstraZeneca performed. Considering this alternative method validation approach, I don’t anticipate any regulatory approval issues associated with the results generated.?

Which countries do not include rapid sterility in their pharmacopeia??

Unfortunately, I don’t have a full background of each country’s pharmacopeia, but most influential pharmacopeia include at least some references to alternative micro methods. Based on feedback from our customers and their approval in nearly all countries, I assume if a nation’s pharmacopeia does not include alternative method references, the local regulatory agency is still capable of granting approval.?

Some questions were clearly directed towards my counterpart on this webinar, Sophie Drinkwater. I encourage you to access the webinar on-demand and check out her presentation. Sophie addressed many of these points at the end of our presentations. However, I’ll speak on feedback I’ve received from Celsis users in the industry:?

• Has AZ used this method in lieu of traditional culture methods for any recent filing??

• What have regulators challenged you (or been supportive of) on when presenting to them the intention to launch Celsis in a Type C style meeting???

• How likely is a regulatory body to accept this alternative method? In Europe, is it easily accepted???

I am aware of several Celsis users who have been granted regulatory approval to use Celsis for routine sterility release testing. This method is included in recent filings and replaces the need for the traditional test.??

Recently, regulatory agencies have been very accepting of product filings with Celsis provided that sufficient laboratory validation work is complete. One of the most common question users receive from regulatory agencies is “What did your inspector from (insert other international agency) say when they reviewed this?”. In these cases, the customers received approval with minimal pushback on the data presented.?

One of the early adopters for Celsis submitted primary validation data using tween as a surrogate product. The FDA asked that user to provide data using one of the manufacturer’s actual products. Using a product manufactured at that site better supports the FDA’s notion of “Validation for intended use.” The user repeated the validation with that data and had no other issues associated with equivalency data.??

As a final note, in my conversations with FDA inspectors, they highly recommend type C meetings if your site is looking to bring in a rapid method. At this meeting, you can establish what validation data is needed for your network. You can also understand what data from one of your products can be used to support the method for additional products in your portfolio. In many of these cases, generated equivalency data for one product is acceptable for supporting all other products at your site, as long as product specific method suitability testing is performed.?

It's amazing to see the interactions between rapid method vendors, users, and regulatory agencies as they work together to ensure safe product is delivery to patients. Every month Charles River Laboratory completes a validation study with customer products and environmental isolates, further cementing the broad equivalency of this technology to the traditional method. The attitude towards alternative methods is quickly changing as this data is generated.?

If you would like to learn more on how to generate this data for your products, we are happy to help.?

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Author: Jon Kally