Planning a legacy molecule transfer
Once a company makes the decision to transfer a legacy or mature process to a backup manufacturing site, it should consider
the key aspects of the process illustrated in Figure 2. A successful technology transfer must have a successful conformance
campaign (also referred to as process performance qualification or process validation lots), in which the company demonstrates
process consistency and product comparability and gains regulatory licensure. The first and foundational strategy is thus
to carefully scope process and method changes and improvements that might affect the success of the conformance campaign.
It is generally accepted that the primary and backup manufacturing sites should have the same process chemistry, and that
changes should be minimized to avoid process drift. Any process improvements should be deferred to after implementation of
the site transfer, and even then should be done in concert between the primary and backup sites to ensure process alignment.
Ideally, the process scale should also be kept the same, but in some instance this may be challenging based on facility and
equipment constraints and a desire to minimize the capital outlay for such a site-transfer project. Method changes are another
concern. If a company decides to use this as an opportunity to remediate and modernize methods, it should allocate sufficient
resources and time for these activities. The newer methods may be more sensitive and may reveal the presence of impurities,
which, once identified, should be characterized. Care should be taken in changing specifications or process controls, as this
could make the site transfer more challenging.
Figure 2: Several aspects must be considered in the legacy molecule transfer process.
The company should consider several key questions that may impact the scope, cost and timeline for implementing the project
and establishing engineering design objectives:
- Will the secondary facility be used for regular commercial production or purely as a backup?
- How many lots (i.e., engineering runs) will be required to shake-down the process?
- How will the process be validated?
- What is needed to maintain commercial licensure status?
Finally, the company should consider the regulatory landscape. Typically, site transfers are submitted using a prior approval
supplement (PAS). Alternate regulatory strategies, such as a comparability protocol or Changes-Being-Effected-30, may be considered,
depending on the complexity of the transfer and scope of potential changes. Bundling changes, such as method remediation or
specification changes, with the site transfer could increase the complexity and make first-time approval more difficult to
obtain. Legacy molecule transfers must deal with the challenge of staying current with evolving regulatory, quality, and operating
The following section describes in more detail a few of the major challenges of legacy molecule transfers and strategies to
deal with them.