PAT Initiative Next Steps Ajaz S Hussain Ph

PAT Initiative: Next Steps Ajaz S. Hussain, Ph. D. Deputy Director Office of Pharmaceutical Science, CDER, FDA

PAT Initiative • FDA Science Board Meetings (11/01, 4/02) – Emerging Science Issues in Pharmaceutical Manufacturing • Current state of Pharmaceutical Manufacturing – G. K. Raju (M. I. T) and Doug Dean (Price. Water. House. Coopers) » Opportunities for improvements – Norman Winskill and Steve Hammond (Pfizer) » New Technology - “Don’t Use” or “Don’t Tell” approach – Ray Scherzer (CAMP/Glaxo. Smith. Kline) » Challenge to Phrama Industry - Quality By Design – Science Board support for FDA’s proposal to facilitate innovation http: //www. fda. gov/cder/OPS/PAT. htm#scienceboard

PAT Progress • Advisory Committee for Pharmaceutical Science (PAT Subcommittee) deliberations – – Definitions, benefits, and scope Perceive/real regulatory “hurdles” Internal (with-in company) “hurdles” Need for across discipline communication • Pharmacy+Chemistry+Engineering = Pharmaceutical Engineering – – Approaches for removing these “hurdles” Case studies General approaches for validation PAT Training curriculum for FDA staff

PAT Teams: 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 Policy Development Team Raj Uppoor, OPS/CDER Chris Watts, OPS/CDER Huiquan Wu, OPS/CDER (Ali Afnan, OPS/CDER) PAT Training Coordinators John Simmons, Karen Bernard and Kathy Jordan PAT Review - Inspection Team Investigators: Robert Coleman (ORA/ATL-DO) Rebecca Rodriguez (ORA/SJN-DO) Erin Mc. Caffery (ORA/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)

Why Process Analytical Technologies? • PAT provides an opportunity to move from the current “testing to document quality” paradigm to a “Continuous Quality Assurance” paradigm that can improve our ability to ensure quality was “built-in” or was “by design” - ultimate realization of the true spirit of c. GMP! – – Greater insight and understating of processes At/On/In-line measurement of “performance” attributes Real-time or rapid feedback controls (focus on prevention) Potential for significant reduction in production and development cycle time – Minimize risks of poor process quality and reduce (regulatory) concerns

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

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

Regulatory Framework • PAT tools not a requirement • Research exemption – Continuous improvement without the fear of being considered non-compliant • Regulatory support and flexibility during development & implementation – Eliminate the fear of delayed approval – Dispute avoidance/resolution • Science & Risk based regulatory approach – Low risk categorization based on a higher level of process understanding

Strategy for Moving Forward • Scientific Workshops – Several FDA co-sponsored and other workshops conducted (US and Europe) – Scientific discussion and debate • across disciplines (pharmacy, chemistry, chemical engineering) • organizational units (development, manufacturing, quality control, and regulatory departments) • General guidance on PAT to be released – Training workshop – Bring together different Associations (disciplines)

Strategy for Moving Forward • Champions to drive this initiative towards a “shared vision” or “desired state” – Industry: Pfizer, GSK, BMS, Aventis, Lilly, Novartis, . . . – Academia: MIT, Purdue, Washington, Tennessee, Michigan, Rutgers, Maryland, Minnesota, Connecticut, Puerto Rico, Duquesne. . , London, Bradford, Basel, … (planned - Gifu and other universities in Japan) • PAT introduced in Pharmaceutical Engineering programs at Purdue, Michigan and Rutgers – (Instrument vendors - moving towards an association to address common issues)

Strategy: Moving forward • Improving the FDA knowledge base for technical policy development – Several experts recruited – Intramural research refocused to address technical needs and for in-house training • Significant increase in peer reviewed contributions – Learn from other industries (e. g. , link with ASTM) – CRADA with Pfizer developed, awaiting final FDA approval (focus on chemical imaging) – Collaborate with NSF (Center for Pharmaceutical Processing Research)

Strategy: Moving forward • PAT Initiative a part of the broader c. GMP Initiative for the 21 st Century (announced 12 August 2002) – An example of science and risk-based systems approach to product quality regulations

Strategy for Moving Forward • Post approval implementation of PAT – PAT-Comparability protocols proposed by several companies • systems thinking, process understanding, risk mitigation strategies - Manufacturing Science – PAT Review & Inspection team • training and certification • science and risk based review and inspection – Product Specialist on inspection concept • Expertise: Industrial pharmacists, chemical engineers, chemometric, process analytical chemistry

Move from “testing to document quality” to “quality by design” • What does this mean? – Effective methods for managing/controlling (particle size) variability to provide consistent performance – Establishing causal links between material attribute (particle size) variability and performance – Reduce reliance on lab-based test methods • Improve focus on process understanding as compared to “test” comparisons

Risk = ? • Change = Risk(? ) – Section 116 of the Modernization Act section 506 A (21 U. S. C. 356 a) the Food, Drug, and Cosmetic Act (the Act) – ……. potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product (506 A(c)(2)). – Substantial Potential - PAS – Moderate potential - CBE-30 Days or CBE – Minimal potential -AR

Risk Based Review • Review - minimizes intolerable risk to patient safety • Process – Identify risk scenarios – Assess likelihood of fault condition – Assess severity of impact – Assign risk grade – Assess probability of detecting fault condition – Determine mitigation strategy

Quality Risk Scenarios • Risk of unacceptable quality (examples) – Releasing a unacceptable quality product • Inadequate controls/specifications – “New” impurities – Bio-in-equivalence • Inadequate process validation – sampling not “representative” – Stability failure – Bio-in-equivalence – Poor Process quality – Others

Risk of Bio-in-equivalence • Risk factors – Manufacturing changes pre/post approval • minor - moderate - major changes – Poor process capability • high between and within batch variability – Reliance on in vitro dissolution tests • single point specification - sampling - predictability – Other factors • deficiencies in BE study design - Type II error Bioequivalence - one of the critical links between quality and S&E

BCS a tool for risk management • Assessment of risk – What is the risk of bio-in-equivalence between two pharmaceutical equivalent products when in vitro dissolution test comparisons are used for regulatory decisions? • Likelihood of occurrence and the severity of the consequences? • Regulatory Decision – whether or not the risks are such that the project can be persued with or without additional arrangements to mitigate the risk • Acceptability of the Decision – is the decision acceptable to society?

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

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

A Perspective on PAT: One piece of the puzzle • “Vision 2020 - I can see clearly now” – Quality & performance by design + Continuous “real time” monitoring of quality – Specifications based on mechanistic understanding of how formulation and process factors impact product performance – High efficiency and capacity utilization – Science based regulatory decisions focused on product and process quality http: //www. fda. gov/ohrms/dockets/ac/01/slides/3804 s 1_02_hussain. ppt

PAT = Process Understanding Risk based Regulatory Assessment Intended Use 1 st Principles Modeling Optimization Continuous Improvement (including CAPA)