Office of Pharmaceutical Science, CDER, FDA ACPS Process Analytical Technology (PAT) Subcommittee Meeting #3 Opening Remarks Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science, CDER, FDA

Outline Update on FDA progress PAT Team Blend uniformity and its link to PAT Manufacturing Subcommittee What have learned from the PAT Subcommittee discussions? PAT Conceptual framework and regulatory incentives What information are we seeking today?

Progress Report PAT Review - Inspection team assembled ORA, CDER, and CVM Successful team-building meeting Training curriculum developed and contracts established (Univ. Washington (CPAC), Univ. Tennessee (MCEC), and Univ. Purdue) PAT Policy Development Team Successful recruitment PAT Research Publications and presentations

PAT-Review & Inspection Team: ORA, CDER & CVM PAT Steering Committee Doug Ellsworth, ORA/FDA Dennis Bensley, CVM/FDA Mike Olson, ORA/FDA Joe Famulare, CDER/FDA Yuan-yuan Chiu, CDER/FDA Frank Holcomb, CDER/FDA Moheb Nasr, CDER/FDA Ajaz Hussain Chair, CDER/FDA PAT Review - Inspection Team Investigators: Robert Coleman (ORA/ATL-DO) Rebecca Rodriguez (SJN-DO) Erin McCaffery (NWJ-DO) George Pyramides (PHI-DO) Compliance Officers: Albinus D’Sa (CDER) Mike Gavini (CDER) William Bargo (CVM) Reviewers: Norman Schmuff (CDER) Lorenzo Rocca (CDER) Vibhakar Shah (CDER) Rosario D’Costa (CDER) Raafat Fahmy (CVM) PAT Policy Development Team Raj Uppoor, OPS/CDER Chris Watts, OPS/CDER Huiquan Wu, OPS/CDER PAT Training Coordinators John Simmons, Karen Bernard and Kathy Jordan

Lyon, et al. Near-Infrared Spectral Imaging for Quality Assurance of Pharmaceutical Products: Analysis of Tablets to Assess Powder Blend Homogeneity AAPS PharmSciTech 2002; 3 (3) article 17

Blend Uniformity & PAT Univariate Testing to Document Quality Approach Traditional test methods Current PQRI proposal and draft Guidance Draft Guidance may include information on the use of NIR methods At-line test methods On- and/or At-line test methods for all critical components and processes Proposed PAT Guidance Incentive? Higher efficiency Lower “risk” leading to lower regulatory concern Multivariate Quality-by Design Approach

Manufacturing Subcommittee Provide input/advice to CDER/FDA Science based CMC and cGMP policy development Continued development of the PAT initiative cGMP for the 21st Century: A Risk Based Approach

Manufacturing Subcommittee Modeled after the PAT Subcommittee Core membership based on expertise in manufacturing and quality assurance Some members of the PAT subcommittee will be invited to participate (sunset PAT Subcommittee) Focused working groups or fact finding groups (sunset after assignment is completed)

In-put from ACPS PAT-Subcommittee Conceptual framework on PAT Emerging regulatory incentives for PAT Research exemption Risk based regulatory focus, opportunity to reduce regulatory burden PAT as a part of, and a example of, the new FDA wide initiative “cGMP for the 21st Century”

PAT: Conceptual Framework Incoming Materials. Specifications Relevant to “Process-ability” Incoming material attributes used to predict/adjust optimal processing parameters within established bounds (more flexible bounds) PAC PCCP LT CM IT Direct or inferential assessment of quality and performance (at/on-line) Control of process critical control points (PCCP). Process end point (PEPs’) range based on “performance” attributes. PEP’s Chemometrics (CM) and IT Tools for “real time” control and decisions At-line In/On-Line Process Analytical Chemistry Tools Laboratory or other tests Development/Optimization/Continuous Improvement (DOE, Evolutionary optimization, Improved efficiency) Multivariate Systems Approach Risk Classification and Mitigation Strategies

Taking Advantage of Built-in Redundancy? General Quality System Product specific SOP’s,... PAT Based Measurements and Controls Systems Approach Validation Taking Advantage of Built-in Redundancy?

Product and Process Quality Knowledge: Science-Risk Based cGMP’s Quality by Design Process Design Yes, Limited to the Experimental Design Space Maybe, Difficult to Assesses GMP/CMC FOCUS Design qualification Focused; Critical Process Control Points (PAT) Extensive; Every Step (CURRENT) DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION DECISIONS BASED ON UNIVARIATE APPROACH CAUSAL LINKS PREDICT PERFORMANCE MECHANISTIC UNDERSTANDING 1st Principles

Quality Risk Priority Probability of Detection Medium Low High 3 Quality by design + Systems approach Probability of Detection Low Medium High High 3 Medium Risk Classification 2 1 Low

Quality Risk Classification (based on SUPAC and GAMP-4) Quality by design + Systems approach Risk Likelihood High Medium Low Level 3 Level 2 Impact on Quality Level 1

Appropriate labeling and risk management PAT: Connecting-the-Dots Development - Manufacturing:: Review - Inspection Appropriate labeling and risk management Discovery Development Review Marketing Pre-clinical Clinical I, II, III Approval IV AER’s Pre-formulation Formulation (Clinical) (Optimization) Optimization Scale-Up Manufac. (For Market) Changes Appropriate Controls & Specifications Building Quality In ? Safety & Efficacy (“Make Your Own SUPAC”?) (Interim Spec?) (Final Specs.?)

Today we seek information on Computer software validation Several excellent guidance documents exists CDRH, GAMP-4, others (?) We plan to adopt and/or refer to some of these in the PAT guidance What additional considerations would you recommend for PAT guidance?

Today we seek information on What aspects of 21 CFR Part 11 need clarification for PAT applications? Note that Part 11 applies to all systems generating electronic records We wish to focus our discussion within the context of PAT

Data elements to be acquired and stored? What incoming material data elements should be acquired, e.g., NIR? What incoming material data elements should be retained, e.g., matches spectrum, full spectrum? What in-process data elements should be acquired, e.g., image fields for homogeneity monitoring? What in-process data elements should be retained, e.g., meets acceptance criteria, retain final pH value or all values measured? What product release data elements should be acquired, e.g., individual tablet NIR or Raman spectra? What product release data elements should be retained, e.g., passes, all data elements?

Today we seek information on Case Studies - Regulatory challenges and solutions “Mock” submissions Rapid Microbial Testing How should this be addressed in the PAT guidance?

Current State Product quality Process quality Based on the small number of recalls due to product quality, we probably are already close to Six Sigma level of quality Process quality Ranges from poor to good Poor process quality can have a catastrophic effect on the reputation and economic health of a company Poor process quality can lead to drug shortages

It is the Right Time to Focus on Process Quality Higher level of process quality is desirable from both public health and business perspective Reduce risk of releasing a poor quality product Reduce regulatory risks and costs Reduce time-to-market Reduce stress and frustration Today we can be proactive

How? Most pharmaceuticals are complex, multivariate, physico-chemical systems Have to rely on iterative empirical development approach - guided by a formulators experience Mathematical optimization would require use of Response Surface Methodologies Subjective measures of material functionality Many variables and long waiting periods for lab data Not enough time and/or material available No regulatory incentive for formulation/process optimization

Why Transforming Efforts Fail Not establishing a great enough sense of urgency Not creating a powerful enough guiding coalition Lacking a vision Under communicating the vision by a factor of ten Not removing obstacles to the new vision Not systematically planning for and creating short-term wins Declaring victory too soon Not anchoring changes in the corporation’s culture

Thank You See you at Arden House US Arden House UK IFPAC