Global experiences
Wyeth submitted MAs for Products X and Y to the regulatory authorities of the European Union, Australia, South Africa, Canada,
and several other markets outside the United States. The company requested a meeting with the European Medicines Agency (EMEA)
PAT working group to discuss its planned QbD approach before submitting the MA for Product X. Members of the EMEA PAT working
group and rapporteurs were present at the meeting, which led to a common understanding of the developmental approach using
QbD principles. Besides these discussions, there were no formal opportunities for scientific interchange during the review
process. A similar approach was taken with the Canadian submission. Wyeth's QbD strategy was discussed at a pre-new drug submission
meeting.
In a majority of the other markets, formal processes for scientific interactions before the submission or during review may
not exist. Therefore, clarifications of the QbD strategy were provided in writing upon receipt of Board of Health queries.
Global understanding of applications of QbD by all reviewers is, at times, variable.
The MAs submitted to regions outside the US required a traditional Quality Overall Summary (QOS), as opposed to the comprehensive
QOS that was required by the FDA CMC Pilot Program. In addition, because a framework for the comparability protocol does not
exist in other regions, Wyeth did not include its RTR proposal in international MAs.
The review of the MAs and the interactions with regulators were beneficial to Wyeth despite the traditional approach. A majority
of the agencies posed primarily science-based questions. In a few cases, however, the review was very traditional and the
expectations of the agencies were sometimes inconsistent with ICH Q8, Q9, and Q10. In such cases, the application had to be
modified to incorporate traditional control strategies.
Lessons learned
Wyeth learned several lessons during the submission and review process for its Products X and Y applications for the CMC Pilot
Program and for international MAs, as outlined below.
Comprehensive QOS.
The feedback received during the NDA review indicated that the contents of the comprehensive QOS were important. The QOS
ultimately served as the roadmap and launching point for the review of the dossier. Clear presentations, including tables
and pictures that showed results, allowed the reviewer to reach the fostered conclusions. Wyeth found that the QOS document
should be concise, emphasizing the data and providing conclusions based on data analysis. The document also should highlight
the process used for the identification of CPPs, CMAs, and so forth.
Wyeth's experiences with the CMC Pilot Program and the submission and review of MAs in other regions of the world indicate
that a traditional QOS as described in ICH M4Q (R1) on the common technical document (9) may be needed for some markets, while
others may accept the comprehensive QOS, the contents of which may exceed the requirements specified in the harmonized guideline.
Development report.
The primary goal of QbD is to adopt a structured approach to yield a deeper product and process understanding. Regulatory
flexibility may be an outcome. Wyeth found that this goal of understanding needs to be driven home in development reports.
To increase the reviewer's confidence in the application and facilitate a smoother review, the expanded Pharmaceutical Development
Report (3.2.P.2) section for the drug product and an expanded drug-substance manufacturing process module (3.2.S.2.6) should
demonstrate the enhanced product and process understanding by including the following information for various experiments:
rationale, data summaries, analysis of data, and conclusions drawn from all experiments. Expanded development reports increase
the reviewer's confidence in the applicant's ability to reliably and consistently manufacture quality drug substances and
drug products.
|
