PhRMA Perspective on FDA Final Report FDA Advisory Committee on Pharmaceutical Sciences October 20, 2004 G.P. Migliaccio, Pfizer Inc

Discussion Topics Culture Change General Comments on Report Quality Systems Guidance Risk-Based Inspection Model ONDC Risk-Based Quality Assessment System Summary

Three Years of Culture Change An unprecedented period of communication and learning for both FDA and Industry. The culture change has been driven by open communications and a shared vision of the desired state. PAT was the model, much has followed.

Two Years of Culture Change Industry is moving from a fear of data to a passion for process understanding. Science, not blind compliance, is winning the day more often. Innovation is accelerating throughout industry. Interactions during inspections are changing.

General Comments on Final Report This is not the end, it is the beginning! PhRMA applauds the magnitude of what has been accomplished and the rigor in which it was accomplished. FDA and Industry Leadership must continue to work together to ensure that the guidance and position papers are fully understood, modified as appropriate, and implemented. Much remains to be accomplished to realize our shared vision.

Quality Systems Guidance Comprehensive and of great utility. Companies are already using to assess Quality Systems infrastructure. Key outstanding issue is defining the level of process understanding required to achieve flexible continuous improvement. Imperative that these concepts be addressed at global level and the FDA guidance provide a starting point for ICH discussions relative to the proposed Q10.

Quality Systems Guidance FDA and Industry must move away from current “Compliance Systems” to be able to achieve all elements of Quality Systems Guidance.  e.g. Trending of data  Some data generated for compliance purposes can not be trended to gain process understanding.  Current specification system must evolve to allow reporting of meaningful data on CTQs.

Risk-Based Inspection Model Solid step forward to allow FDA to focus on higher risk sites. Elements of the algorithm require further discussion – e.g. volume. PhRMA has serious concerns about transparency.

Risk-Based Inspection Model “Survey results were analyzed and process control and contamination weights were assigned to each product category identified in the expert elicitation survey.” “Individual risk-factor weights and final scoring information, as well as specific information used to generate the weights and scores, are intentionally not provided in this paper. FDA does not intend to publish or disclose such details of a site’s individual score or ranking, in order to effectively enforce the law.”

Risk-Based Inspection Model “FDA’s customer relationship with industry will differ depending on the transactions involved. At one end of the spectrum, industry clearly is a direct customer of FDA’s products or services. For example, when FDA develops guidance documents representing the agency’s current thinking on a particular subject, we provide clarity and understanding to firms that manufacture FDA regulated products. With this information, industry has a better understanding of the agency’s expectations about their products, and this may enable companies to manufacture products more effective or approach regulatory milestones with greater certainty.” From Defining the Customer in a Regulatory Agency, Appendix B

Risk-Based Inspection Model “FDA will now be using a Quality Systems approach to improve the predictability, consistency, integration and overall effectiveness of our entire regulatory operation.” from “Final Report”

Risk-Based Inspection Model If FDA and Industry do not have a mutual understanding of what processes/unit operations are higher risk, how can FDA and Industry appropriately focus their respective resources on high risk areas? Transparency is essential.

ONDC Risk-Based Quality Assessment System Represents a profound change in the organization and review process. PhRMA supports the objective, but much work is required to achieve the end state. Will FDA approach this change with the same level of leadership commitment and reviewer availability as demonstrated with the PAT and GMP initiatives? Will FDA work with industry to ensure that the objectives can be achieved?

ONDC Risk-Based Quality Assessment System ONDC proposal could create expectations that there will be a significant increase in the knowledge provided “up front”.  Companies will provide different information resulting in a greater degree of process understanding, but at NDA submission, the level will be limited.  Process knowledge will be sufficient to establish that a robust process has been developed.  Process understanding is a continuum, and will accelerate post approval.

ONDC Risk-Based Quality Assessment System FDA should work through ICH to establish a global partnership for the risk-based quality assessment system. We should not exacerbate the current differences in assessment systems but work to establish a global assessment approach.

ONDC Risk-Based Quality Assessment System Pre- and Post-Marketing approach requires further evaluation. Process understanding significantly increases during first 1-2 years of marketing and potential for continuous improvement is highest. There is value to having the NDA reviewer also review these continuous improvement changes.

ONDC Risk-Based Quality Assessment System FDA has implied that there will be two assessment systems, one for applications including manufacturing science/process understanding, the other without.  Process understanding is not a “yes” or “no”, it is a continuum.  Every application will have a different level of process understanding.  How will a reviewer determine where any application is in this continuum?

Summary The infrastructure is in place – some modification required. The culture is changing. The desired state is on the horizon.