What do you need to do when you need to change suppliers or manufacturing sites? Among the many choices is a formal FDA comparability protocol.

Advance planning can improve the possibility that the FDA accepts your proposed change. One alternative that can streamline the process of change and add clarity to the requirements involves preparing a comparability protocol to be included in the NDA submission. The following scenario outlines alternative strategies to support a manufacturing site change. If the sponsor has enough information to prepare an acceptable comparability protocol, this can be the most efficient route to support the change. A scenario is provided below to compare the strategies and requirements for a Level 3 manufacturing site change after NDA approval.

Background for Manufacturing Site Change

Two manufacturing sites are being considered for a non-sterile semisolid commercial product. At the time of the NDA, one will be defined as primary (Site A) and one will be defined as an alternative supplier (Site B).

At the time of the NDA a demonstration batch manufactured at Site A will be submitted, accompanied by an executed master batch record, and a proposed batch record for commercial production. Along with this it will be necessary to provide the Certificate of Analysis for the batch, and stability data. This would mean that Site A would be scheduled for a PAI once the NDA has been submitted.

Questions:

1. What information should be submitted if, after NDA approval with Site A, the alternative manufacturer – Site B – is then made the primary manufacturer?
2. What type of submission would this be?

Assumptions

(See Non-sterile Semisolid Drug Formulation, SUPAC: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation, May 1997)

• All equipment is equivalent between Site A and Site B.
• The process and scale are the same between Site A and Site B. The order of mixing has not been altered, the completeness of mixing is consistent, and the hold time for the product prior to packaging is not altered.
• The product components and specifications are the same between both sites.
• The product produced at both sites meets the same release criteria.
• The product stability is the same between both sites.
• The biological activity (in vitro test) is the same for the product produced at both sites.
• The agency can ask for more information than provided in any supplement if needed.

Options

(See Changes to an Approved NDA or ANDA, April 2004 )

1. A manufacturing site change from Site A to Site B after approval can be be effected with a change being effected (CBE) submission.
   • This is true if:
     • Site B is currently manufacturing the same dosage form under cGMPs.
     • Site B’s cGMP inspection history with the FDA is satisfactory, and inspections have included the manufacturing line to be used for this product.
   • A CBE submission should include:
     • A Certificate of Analysis from a batch manufactured at Site B demonstrating that compendial release requirements are achieved.
     • The in vitro testing to qualify the demonstration batch should be supplied comparing this new batch from Site B to the batch submitted from Site A.
     • An executed batch record from Site B.
     • Three months of accelerated stability from the first batch manufactured at Site B compared to the accelerated stability from the Site A batch(es).
     • An Annual Report should include updates on long-term stability from the first three batches manufactured at Site B compared to the long-term stability of batches manufactured at Site A.
2. The submission after approval will be a prior approval supplement (PAS) if:
   • Site A has not had a satisfactory FDA inspection for cGMPs.
   • Site A does not have a history of manufacturing this dosage form.
3. A comparability protocol can be submitted in an NDA and if accepted will allow the manufacturing change under that protocol to be submitted in the Annual Report.
   • Should be used within the context of sponsor’s Change Control System
   • Description of the planned changes
   • Specific tests and studies to be performed
   • Analytical procedures to be used
   • Acceptance criteria
   • Data to be reported under or included with the comparability protocol
   • Proposed reporting category
   • Equivalence not demonstrated using the approved comparability protocol
   • Commitment

Choosing to file a comparability protocol allows the sponsor to plan for potential changes, allowing for more efficient planning of time and budgets. In this scenario, the change is implemented under the internal change control process and comparability protocol and upon meeting all the established acceptance criteria the commercial product can be released for use. This protocol can be a powerful tool for the sponsor if it is written appropriately and the product development has been well-studied.