The process and product understanding discussions established a platform for the review of the comparability protocol for
RTR implementation. Topics addressed during these interactions included the rationale for the choice of the process analyzers;
development, validation, and maintenance of chemometric models; and acceptance criteria for RTR tests and their correlation
to the regulatory specifications and sampling plans.
FDA's guidance for industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, does not address PAT approaches (8). Therefore, Wyeth and FDA extensively discussed the approach for handling out-of-trend,
OOS, reaction modes, management of PAT failures, and alternate approaches to release product when such events occur. The parties
also discussed batch disposition in the PAT environment.
For Product Y, Wyeth concentrated the QbD work on the impurities and degradation of the drug substance and then linked this
information to the degradation of the drug product. Wyeth conducted in-depth analyses of the synthetic steps and crystallization,
evaluated the root causes of the formation of impurities and degradation products, and established controls of the CPPs to
minimize those impurities and degradation products in the drug substance. Further controls beyond compendial testing were
placed on an excipient to minimize the potential formation of degradation products in the drug product.
Preapproval inspection and preoperational visit.
A field inspector and two reviewers from FDA's Office of New Drug Quality Assessmement participated in the PAI for Product
X. The inspection was science- and risk-based with a strong focus on the quality systems for QbD implementation. Topics discussed
during the PAI included systems for QRM implementation at the manufacturing site, change controls, corrective action/ preventive
action (CAPA), product and process monitoring, and the implementation of design space.
Development and operational personnel from Wyeth were involved in the PAI. The development personnel led discussions related
to the pharmaceutical development (process and product understanding), while the site's operational personnel led discussions
about the quality systems and implementation of QbD within the site. The POV was made by three employees from the Center for
Drug Evaluation and Research (one from the review division, one from the Office of Regulatory Policy, and one from the Office
of Compliance) and three from the field (two from the district and one from the PAT team). The discussions were science- and
risk-based with an emphasis on the quality systems for the implementation of PAT and RTR at the site. Specific talks focused
on:
- Disaster recovery systems in the event of PAT failure, including the implementation of alternative tests, sampling plans,
and justifications to demonstrate that the alternate tests would provide the same level of assurance as the RTR mode
- Systems for chemometric model development, validation, and optimization in the production environment
- Systems for tracking and trending data
- Batch-release processes in the RTR environment.
The PAIs for Product Y were conducted at the drug-substance and drug-product manufacturing sites. Two reviewers participated
in the inspection at the drug substance site because the QbD work was focused there. The inspection assisted in clarifying
the definition of the starting materials and the synthetic process flow.
Overall regulatory assessment.
Wyeth's experience during the CMC Pilot Program review was positive. The open communication with FDA resulted in several
scientific discussions that led to a common understanding of various topics. The agency's centralized coordination of the
two NDAs for Product X under one CMC review team enhanced overall efficiency and avoided duplication of efforts for FDA and
the sponsor. The POV served as an opportunity to obtain feedback on the modifications to the quality systems that were based
on science-and risk-based approaches.
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