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Stability Requirements in the 505(b)(2) Space: Why, What, When, How

Hurry up and wait. That’s the seemingly eternal impact of developmental stability on the new drug development process. The question always asked is: “How can the developer minimize the wait part?”

At the top level you can’t. It will always take six months to get six months of data and twelve to get twelve. But you can lessen the impact with early, thorough planning, starting soon after the development of the initial Target Product Profile.

It is key to remember that the 505(b)(2) is a NDA (as opposed to an ANDA) and carries all associated data requirements of the NDA. The stability prerequisite and overall product development timeline reflect the NDA level of requirement. That timeline can often be compressed compared to the standard NDA, but is almost invariably longer than for an ANDA.

In general, for a 505(b)(2) submission, the API is well characterized (including stability) so this blog will focus on the new drug product stability.

Product Stability Testing

The stability program starts in the analytical lab with the development of the test methods for the new product.  It may be that, for the 505(b)(2) candidates, the methods already exist, particularly assay, and if the reference drug is a solid oral dosage, dissolution.

If so, go with it, the biggest issue in this case will be method specificity in the presence of different excipients. The related substance method is key, as the first concern FDA will have is the stability and safety of your product at the phase 1 stage. A forced degradation study should be undertaken as soon as the formulation is chosen. This will identify the important degradation products that will need to be characterized and possibly qualified. Identification of these stability indicating parameters and development of test methods as soon as possible is critical to lessening the impact of stability studies on the development timeline. The earlier a to-be-marketed formulation is established, the sooner pivotal clinical studies can be run, allowing for parallel clinical and CMC development and making the overall development process more efficient.

Differing Requirements at Different Phases

To get to phase 1, the only stability required is some leading studies on the clinical trial material: make it, bottle it, store it, and test it. These studies can lead the clinical initiation by as little as one month, but it is good to have both long-term and accelerated studies ongoing. Most likely, the clinical trial material (CTM) batch size will be too small to qualify as a registration batch, but the concurrent stability will be necessary to support that formulation for the course of the phase 1 trial. (Note: there are examples where the CTM can be the pilot batch for registration, these must be carefully planned). The FDA recognizes that drug development occurs on a continuum rather than in discreet steps, and expects that the analytical development associated with the stability program is progressing accordingly and in step with the clinical development.

For phase 2, available stability data for the clinical material used in the phase 1 study that were not reported during phase 1 should be provided in an information amendment. Stability data for representative clinical trial materials used in phase 3 should be provided. If not already completed, stress studies should be conducted during phase 3 to demonstrate the inherent stability of the drug substance, potential degradation pathways, and the capability and suitability of the proposed analytical procedures. These stress studies should include photostability studies and freeze-thaw cycling studies.

The caveat to products developed under the 505(b)(2) pathway is that these programs may only require Phase 1 studies, meaning that methods may need to be established, and testing completed, earlier than would be done in a standard 505(b)(1) development program. If this is not done, additional bridging studies may be required to link earlier work with registration batches to support approval.

Stability Data at Submission

For submission of the NDA, the requirement is for 6 months of data from product stored and tested under accelerated conditions (40°C/75%RH), and twelve months for the long-term studies (25°C/60%RH). In some instances (when agreed to by FDA ahead of the submission) the agency will accept less than 12 months of long-term data, if you are prepared to accept a shortened expiry dating for your product. Depending on the market launch strategy, this may be acceptable. For example, if you are collecting more stability at longer times at the time of NDA submission/approval, you can use those data to support a post approval extension of the shelf-life (usually an annual reportable event when supporting data are presented).

In the development stage, analytical methods do not have to be fully validated, but you should have confidence in them that they are ‘validatable’; if you make substantive changes late in the development program you may jeopardize the validity of the earlier test results. Analytical methods and procedures should be validated as early as practical in the process to ensure reliability, consistency and accuracy of analytical data.  Method changes that occur after collection of clinical data has begun will need to be appropriately bridged to be applicable to a formulation that may have changed. The pivotal batches to support the registration must reflect the proposed commercial formulation, so it is key to get to this point as soon as possible to initiate the stability studies and to get the ‘brass ring’ of approval as quickly as possible.

Premier Consulting has in-house formulation experts and the capability to lead and support stability data plan development, analysis, and presentation. Contact us to learn more about stability in the 505(b)(2) space.


Robert Kessler, Ph.D.
Senior Director of Analytical Development

Eric Kendig, Ph.D.
Senior Scientific and Regulatory Manager