Regulatory filing and preapproval inspection (PAI)
Following completion of the validation campaign, the data from the validation campaign are consolidated in process validation
study reports. Sufficient time should be allowed to draft and review the Controls, Manufacturing, and Chemistry (CMC) sections
of the regulatory dossier. The roles and timelines to write and review CMC sections should be clearly defined. It is necessary
to ensure that the CMO is aware of timelines for responding to questions from regulatory agencies and that resources are made
available for this activity. A clear communication plan is crucial to ensure that regulatory questions are answered by the
appropriate individuals within a specified time. It is important to prepare early for the PAI so that problems are corrected
before they delay approvals and licensure. Sponsors should consider performing mock audits and sending their subject matter
experts and quality management on-site for the PAI.
Transition to commercial manufacturing
Figure 2. Team structure for technology transfer encompasses strategic and tactical execution. The various technical teams
shown are joint teams and include members from both the sponsor and CMO.
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During the transfer to commercial manufacturing operations, it may be necessary to make some adjustments to the team structure
and level of engagement. One organizational approach that we have found to be effective is to have a virtual site-management
structure as outlined in Figure 3. This consolidates the various sub-teams that were engaged during the TT into a more sustainable
format. The core team is more operational and quality focused to ensure continued success in delivering product to target
metrics for quality, speed, and cost. Oversight via a governance team is still maintained.
From a technical aspect, an important consideration for the transfer to commercial manufacturing is to finalize plans for
process monitoring. The parties should share and document their expectations about which in-process controls will be monitored
as well as the methodology for establishing statistical process control (SPC) limits and identifying process shifts and trends.
They should also agree on how this information should link to quality systems for deviations, change control, and annual product
reviews. It is also important for the parties to agree on the frequency of data review, and how the team responds to SPC
signals so that appropriate corrective action is taken where necessary.
Conclusion
Key to successful TT and a mutual beneficial relationship between sponsor and CMO is clarity in communicating expectations.
Clearly aligned objectives and deliverables and well-defined roles, responsibilities, and team structure from the onset will
lay the foundation for a successful working relationship. There should be appropriate oversight and governance structures
in place. Teams should be mindful of cultural and corporate nuances and use appropriate communication tools, including face-to-face
meetings for milestone project reviews and to build a cohesive team. The need to periodically assess TT and operational risks
and develop contingency plans helps to mitigate such risks. The level of engagement would be expected to evolve depending
on the operational phase, for example, during the transition from TT to commercial manufacturing. Underlying all of this is
a relationship that is built on trust, which improves the speed and cost of doing business and maximizes benefit for both
sponsor and CMO.
Acknowledgments
The authors wish to thank Ali Siahpush and Jian Irish for their insightful comments and guidance in preparation of this manuscript.
SUSHIL ABRAHAM* is director of Process Development, and HOWARD BLAND is a director of Contract Manufacturing, both at Amgen, sushila@amgen.com
.
References
1. E. Langer, Contract Pharma, May 2008.
2. FDA, Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (Rockville, MD, November 2008).
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