The pharmaceutical industry has been trying to become more efficient from both manufacturing and regulatory perspectives.
The challenge is to improve processes, quality systems, and manufacturing capabilities while operating efficiently and in
a manner that ensures safe, effective, and cost-efficient medicines to patients. Many updates to processes and quality systems
can be easily and readily implemented with little or no impact on regulatory filings. However, changes to manufacturing equipment
do affect submissions.
Susan J. Schniepp
Consider the following scenario. A contract manufacturing organization (CMO) making aseptic injectable products is planning
to update one of its manufacturing lines where multiple products from various clients are made. The equipment involved includes
a vial washer, a depyrogenation tunnel, and a filling machine. In addition, a restricted access barrier system (RABS) will
be added around the new filling machine and the automatic tray-off area to increase protection against human intervention.
These equipment updates will impact the regulatory filings of the CMO's clients. The affected clients are notified approximately
six months prior to when the replacement is scheduled. Clients also are informed of the necessary downtime needed to complete
the activities required to ensure that the new line is capable of producing the same quality of product as the previous line
In this scenario, the question most often posed to the CMO from the client is, "What is the recommended filing strategy for
the proposed changes?" To address this question, several points must be considered. One consideration is that the CMO must
adjust its production schedule to ensure that the product reamins available in the market during the scheduled downtime. Avoiding
a drug shortage is particularly important in situations where the CMO is the sole source of the product.
Another item to consider is how well the CMO understands the client's filing with respect to equipment details. The goal of
the CMO in this situation is to be out of commission for the shortest length of time and to propose the most reasonable and
acceptable filing strategy to their clients and the appropriate regulatory agency.
In the most conservative case, these changes might be filed as a prior approval supplement (PAS). However, this approach requires
regulatory agency approval before work can begin and, as a result, could lead to the manufacturing line being down for several
months to a year.
Consider also that the project could take four to six months after approval, including performing the appropriate installation,
operational, and performance qualifications and the process validation requirements needed to requalify the new line. In the
least conservative case, these changes could be reported to the regulator in the client's annual report filing.