The Post-Approval Odyssey: Navigating CMC Changes After Product Launch

While it may seem counterintuitive, there is no less demand for regulatory activities after product approval. There are many changes that can go into effect, and when applied, require shifts in approaches and processes.

Let’s look at regulatory chemistry, manufacturing, and controls (Regulatory CMC) considerations for post-approval changes for products filed in the U.S. In this blog, I unpack common questions around regulatory CMC post-approval activities for various dosage forms and share observations and recommendations. Sponsors should also consider that once a therapeutic has been approved, flexibility to make changes to the approved manufacturing processes is more limited and subject to a different level of scrutiny than during development.

My focus is on post-approval changes specifically related to drug substance (DS) and/or drug product (DP) manufacturing sites and/or processes.

How should a sponsor approach a post-approval change, such as a manufacturing site and/or a process change for a Drug Substance and/or a Drug Product? 

One approach that can streamline the process of change involves preparing a formal U.S. Food and Drug Administration (FDA) comparability protocol to be included in the New Drug Application (NDA) submission. This is the best way to support the change if the sponsor has enough information to prepare an acceptable comparability protocol.  

If the comparability protocol was accepted, it can reduce the reporting category from a Prior Approval Supplement (PAS) with a four-to-six month review time and allow the manufacturing change under that protocol to be submitted as a Change Being Effective (CBE) amendment, typically with review times of either 0 or 30 days, or with the next Annual Report.  This assumes that the new manufacturing site has been recently inspected for similar operations as to what the sponsor is conducting, and that the inspection covered the manufacturing line intended to be used. The reporting category is also dependent on whether the DP is classified as sterile, non-sterile simple dosage form (solid dosage form), or non-sterile complex dosage forms (dry powder inhalers, nasal sprays, or transdermal patches). For sterile and non-sterile complex dosage forms, the risk to the DP quality is higher and therefore, the change may fall under a higher reporting category such as PAS.

The comparability protocol should include information such as a clear description of the planned changes, the specific tests/studies that will be performed to support this change, analytical procedures to be used, the acceptance criteria, and proposed reporting category. The point is to demonstrate the DP quality attributes either did not change from the existing process or are improved, and that there are no adverse changes to the DP quality.

What information should the sponsor include as part of the NDA to support this change? 

As part of the NDA, the proposed commercial site is defined, and the sponsor should at minimum include the following: 

• A demonstration/confirmation of batch(es) manufactured at the proposed commercial site, accompanied by an executed batch record, and a proposed commercial master batch record. 

• The Certificate of Analysis from the demonstration batch manufactured at the proposed commercial site (new site), demonstrating that the product meets all requirements. 

• Three to six months of long-term and accelerated (ACC) stability data from the demonstration batch manufactured at the proposed commercial site will be compared against stability data from representative batches manufactured at the current site. 

• In vitro testing of the demonstration batch(es) manufactured at the proposed new site and comparison with representative batch(es) manufactured from the current site. 

What are examples of post approval changes in the DS and/or DP manufacturing process and/or site and how does the change determine the reporting category the sponsor should approach?

Below are some examples of the types of changes and the reporting category for the respective type the change should be filed under.

Changes in Non-Sterile Product

• If the sponsor is making a fundamental change in the DS and/or DP manufacturing process, such changes should be reported as a PAS. Examples include:
  • Changes in the manufacturing process that may affect the controlled release, metering, or other characteristics of the dose delivery.
  • Any process changes made after the final intermediate processing step in the DS manufacture.
  • Changes that could impact the performance of the DP such as a change from wet granulation to dry granulation process.
  • A change to a new DS supplier. This could be filed as CBE-30. However, if the change is such that the new DS supplier's manufacturing process differs significantly, where the potential for differences in impurities may exist, due to a potential different route of synthesis, process, solvents, or equipment, this should be filed as a PAS, as these changes are major and could affect the DP’s quality and safety.
  • Addition of a component that has never been used in an approved DP (a new ink code imprint, a new excipient).

 Changes for a sterile product

• Changes that may potentially affect the sterility assurance of the drug product will need to be reported as a PAS. Examples include:
  • Changes in the sterilization method (going from terminal sterilization to an aseptic process).
  • Addition, deletion, or substitution of sterilization steps for handling sterile materials.
  • Changes in the sterilizer load configurations that are outside the validated loads.
• Changes related to the equipment could result in filing the change under a PAS reporting category. Such examples include:
  • Addition of new aseptic processing line made with different materials.
  • Replacement or addition of lyophilization equipment.

While tremendous work and energy go into submitting and receiving marketing authorization from the FDA, sponsors should not think that the Regulatory CMC activities will end there. Crucial post approval changes, such as changes to manufacturing sites and/or process for either the DS or DP, should be anticipated and planned for. Ideally, market demand requires increased production volume. Meeting these demands may often include some key changes as outlined in this blog. Having a plan with key points delineated and, ideally, agreed upon with the FDA in advance, will better prepare sponsors for the requirements of commercialization.

If you have additional Regulatory CMC post-approval questions, contact our Regulatory CMC team.