Challenges for mature molecules transfers
Transferring legacy molecules and establishing backup manufacturing capability as part of a geographic diversification strategy
to avoid product disruption raises several challenges.
The strategy for how the backup site will be used impacts the engineering design objectives. A company may decide to use both
the main and backup site for production, or use the backup site only in an emergency. For example, tax incentives or other
financial considerations may favor the use of the primary site. In this instance, the backup site would need to run a limited
number of runs as part of the technology transfer to confirm that the product and process operates in a comparable manner
to the primary site. The backup site would also need to perform a few runs every 3 to 4 years, or as needed, to maintain the
regulatory license. However, in the event of a disruption at the primary manufacturing site, the backup site would need to
ramp up very quickly and be able to maintain the product supply to meet product demand. This emergency scenario requires fast
run-rates and ramp-up times. In addition, while it may be most efficient to run longer campaigns, the need to meet product
demand may necessitate shorter campaigns with more product or host changeovers. Manufacturers should consider these factors
when making design decisions, such as equipment sharing or dedication, facility layout, air handling, personnel and material
flows, use of clean-in-place equipment, and level of automation. A clear guideline is critical for implementing a design that
balances the emergency and regulatory readiness scenarios.
Legacy molecules may have less extensive characterization data than do current molecules that have adopted the design space
concept in the QbD approach. The manufacturer can use historical data, however, from both past characterization studies and
historical manufacturing experience. Good knowledge management systems, by which the techology transfer teams have easy access
to protocols, reports, laboratory notebooks, process monitoring summary reports, campaign summary reports, and annual product
reviews are important. The team should learn from deviations and failed lots at the primary site to understand process sensitivities
and identify where improved controls are required for robustness. The team may need to make minor changes due to facility
constraints. In addition, supplemental characterization studies may be needed to understand the impact of the change on process
performance and product quality. These studies should be carefully designed because they could potentially implicate the existing
process design at the primary manufacturing site.
As mentioned, some process changes may be required due to equipment or facility constraints. The "copy and paste" model (i.e.,
the identical process scale, process chemistry, and procedures are implemented at the receiving site) can be used to avoid
changes that significantly impact the process or product. A rigorous and systematic process for making changes will minimize
the risk of failure. First, teams at both the sending and receiving site should identify potential differences or gaps through
a "facility fit" or "virtual batch" exercise, in which they review in detail how the process would operate at the backup facility
as compared to the primary site. The teams rate the differences based on potential impact to product quality and process (i.e.,
severity) and the likelihood of occurrence. This risk assessment can take the form of a preliminary hazard analysis (PHA)
or failure-mode-and-effects-analysis (FMEA). Once the risks are identified, the team needs to actively manage and mitigate
these risks. The team should document any actions taken to reduce the risk level, and review any new risks identified during
the technology transfer. Any changes made should have clear reasons and preferential changes should be avoided. Changes based
on facility/equipment constraints should be considered against options for additional investment or characterization studies.
A key question is when to introduce process improvements. We suggest that the first order of business is to run the secondary
site's process as closely as possible to that of the primary manufacturing site. Once the secondary site has been successfully
established, process improvements could be made at both sites in tandem, thus avoiding potential process drift problems. When
changes are required, teams can leverage generic data, and also generate supplemental characterization data at the bench,
including wet testing at scale prior to the cGMP runs.
Meeting current regulatory/validation standards.
Another potential challenge in the transfer of legacy molecules is meeting current quality and operating standards at the
secondary site, such as expectations for viral clearance and segregation. While the primary facility may have been "grandfathered-in"
at the time of the original licensure, today's standards require separation between pre- and post-viral areas and at least
one step that provides major viral reduction. Newly licensed sites must also adopt current validation requirements, as published
in the FDA's 2011 updated guidance on the lifecycle approach to process validation. While the original validation package
may not have included statistical approaches to justify the level of sampling or the number of validation lots, for example,
the new validation process must comply.
Establishing statistical process controls.
Continual process verification (i.e., process monitoring) and use of statistical process controls (SPC) provide an early indication
of process trends and ensure continued control of a robust commercial process. Traditional methods for establishing meaningful
statistical control limits, however, typically require greater than 20 runs. If only a few runs are performed every 3 to 4
years at a secondary site, it could take 10 years to establish control limits. Since this is obviously unacceptable to regulatory
agencies, an alternative approach is to consider establishing control limits using the combined data set from the primary
(main) and secondary (backup) manufacturing sites.
Meeting inspection requirements.
At a secondary site, there may be only be a limited window for regulatory inspectors to see the process in operation. The
Executive Order issued by the President, however, does require FDA to work with companies to expedite approvals and avoid
product shortfalls. It is hoped that some relief may be granted with respect to pre-approval inspections. FDA could adopt,
for example, an approach similar to that used by Australia's Therapeutic Goods Adminstration with GMP certification of a facility.
This approach would allow the licensure of the facility for different products to be focused on the supplemental product filings
related to the site transfer. Regulatory inspection requirements can potentially result in an increase in resources required
and hence on the cost and timeline for the successful implementation of the backup facility. Additionally, the team should
carefully think through the impact of inspection requirements on the already licensed primary facility.