Draft Guidance on Biosimilars and Interchangeables Tries to Smooth Path for Post-Approval Changes

There is a growing consensus among legal experts that after Loper Bright, FDA may rely on non-binding guidance to instruct industry with hopes of charting regulatory pathways that avoid litigation. In areas like biologics, biosimilars, and interchangeable biosimilars, where emerging technologies meet regulatory complexities, this is perhaps a wise strategy. The top line from FDA for any cGMP-governed industry like these is always going to be that quality matters. But in the biologics and biosimilar industries, maintaining quality can be a very nuanced—if not difficult—process.

Last week, FDA issued draft guidance to address the potential complications that arise when sponsors seek to modify products, production processes, or quality controls for approved biologics license application (BLA) biosimilar and interchangeable products. Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers Guidance for Industry is intended to be a roadmap that first describes the change notification process outlined in 21 C.F.R. Part 601.12, and then offers additional information and discussion about what FDA expects to see from applicants who are intent on ensuring quality.

The draft guidance first addresses the kinds of information applicants should develop and collect so that they can evaluate the effects that post-manufacturing changes might have on their products’ identity, strength, quality, purity, or potency. Part 601 delineates those changes as being either major, moderate, or minor.

Major changes may have a substantial effect on quality and require a Prior Approval Supplement (PAS). The draft guidance notes that adding a comparability protocol in a PAS that outlines postapproval chemistry, manufacturing, and controls (CMC) changes can be beneficial, potentially paving the way for reduced future reporting if it sufficiently details a minimal risk for adverse effects from the manufacturing changes.

Biosimilar and interchangeable sponsors with moderate post-manufacturing changes can submit a Change Being Effected in 30 Days (CBE-30) supplement. The draft guidance reminds applicants that FDA must approve or note any missing information in a CBE-30 supplement within 30 days before an applicant distributes the product.

Here again though, both the guidance and the regulations describe how a persuasive filing may have advantages for an applicant. A product described in a well-drafted and persuasive CBE-30 might in turn merit immediate distribution, in effect changing a CBE-30 to a CBE-0. The draft refers industry to other guidances on the factors FDA might consider, and the regulation tells us that they include “substantial similarity with a type of change regularly involving a [CBE] supplement or . . . [where] evidence that the proposed change has been validated in accordance with an approved protocol . . . .” In our experience such a change is rare, but perhaps FDA is of the mind here to clarify how this might happen. As for minor changes that have minimal effect of product quality, the draft guidance notes that applicants can document those in their annual report, as opposed to a discreet filing with the agency.

Between the discussion in the draft guidance and the steps described in Part 601, applicants should have useful instruction of how to notify FDA of postapproval changes. But the draft guidance also includes several helpful takeaways for applicants about the kinds of quality data that they should evaluate. For example, it notes that applicants should conduct comparability exercises before and after the manufacturing change and analyze both the data from those exercises as well as their design. That’s because “postchange biosimilar or interchangeable biosimilar product should be evaluated at the process step most appropriate to detect a change in the quality attributes.” As with any cGMP issue, sponsors taking this on also need to focus on process validation.

And since we’re talking about biosimilars and interchangeables, FDA notes that an applicant should include a “well-qualified, in-house reference material.” This is an important “calibration point” for comparability, ideally enabling applicants to evaluate whether the changed product remains sufficiently similar to the reference product.

When applicants introduce a licensed biosimilar or licensed interchangeable product into a multiproduct manufacturing area, they potentially risk cross-contamination, or loss of controls over personnel, process, or materials. The draft guidance notes that in this situation, purity and identity of the product are the key quality attributes at risk. FDA counsels that sponsors evaluate the multiproduct manufacturing risks based on both the type of product and the potential effects of additional controls. In other words, there are no strict guidelines that span across the biosimilar industry.

Finally, the draft guidance describes the CMC information that FDA recommends applicants submit in support of a supplement for a change in dosage form or strength. That information includes adequate comparability data between the original licensed biosimilar or interchangeable and the proposed new dosage form or strength. It also includes an adequate comparative analytical assessment and validated manufacturing data that supports the change.

As is seen here through the myriad regs and guidances we’ve linked, quality assurance for biologics, biosimilars, and interchangeables is a labyrinthine pursuit, and FDA expects to hear about how applicants are ensuring it. We’ll update this post when FDA issues Final Guidance.