The CDER has issued a final guidance titled Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA (here), addressing the role of comparability protocols (CPs) for post-approval changes to the CMC sections of NDAs, ANDAs, and BLAs where the CP is a prospectively written plan for assessing the effectiveness of the control strategy as it relates to the proposed change.  This final guidance is an updated version of the 2016 draft that incorporates comments and current FDA thinking on the requirements for CP contents.

The criteria for determination of the effectiveness of the control strategy will be defined within the CP and will likely be based on identity, strength, quality, purity, and potency comparison data representing drug product (DP) batches pre- and post-change.  A critical component of the CP is a risk assessment of the proposed change and linking the results of the risk assessment to the control strategy (as it relates to managing that risk).

The incentive of submitting a CP to the CDER is that it may provide a justification to report the change(s) with a reduced regulatory reporting burden/category (e.g., PAS would typically be reduced to either CBE-30 or CBE-0), contingent upon analysis of the data from implementation of the change(s).  Justification should be included within the CP for the reduced category and the guidance provides recommendations for sources of such rationale, e.g., process knowledge/development/validation, QRM.  A scientific understanding of the potential impact of the proposed CMC change and how that will manifest in the attributes of the DP must be reflected in the CP, including how such knowledge was incorporated into the protocol’s testing strategy (section IV of the guidance document).  The goal of the testing strategy is to demonstrate effectiveness of the control strategy to address the risk associated with the proposed change.  Testing strategy based upon routine product release testing is unlikely to be sufficient as full characterization of the product pre- and post-change will likely be required.

The CP should reference the DP attributes that are likely to be impacted by the CMC change.  When defining the testing strategy, there needs to be an understanding of the capability of the analytical methods that will generate the comparative test data (including an understanding of the total measurement of uncertainty) as that will need to be considered when defining the protocol acceptance criteria.  In addition, there needs to be confirmation of the method’s suitability to the DP matrix that is generated from both processes (i.e., pre- and post-CMC change).

It is recommended that there is consideration to consulting a statistician when preparing the CP study design as it relates to justification for the number of batches, number of data points, statistical tools for data analysis, acceptance criteria, etc.  For the comparative analysis, it is recognized that the desired output is not necessarily to demonstrate equivalency between the pre- and post-CMC-change data sets as the motivation for the CMC change may well be to improve an attribute of the DP such as its impurity profile (whereupon the CP acceptance criteria would be based on a demonstrated statistically significant improvement of the DP’s impurity profile post-CMC change).

If you have any questions relating to submission of a CP, please reach out to Paul Mason (