US FDA's PAT Guidance – 10 years and now

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Information about US FDA's PAT Guidance – 10 years and now

Published on January 8, 2014

Author: a2zpharmsci



Reflections and Insight on Pharmaceutical Quality, Process Understanding and Human Behavior.

28. und 29. November 2013 in Ludwigshafen am Rhein / Deutschland US FDA’s PAT Guidance – 10 years ago and now 1 Ajaz S. Hussain, Ph.D. Insight, Advice & Solutions LLC 11/28/2013

Insight 2 At FDA the PAT Initiative was a ‘door opener’ to a cultural transformation to prepare for globalization in the 21st Century Cultural transformation takes time and discipline, needs collaborative vocabulary, constancy of purpose, and link to the heart and bottom-line The transformation process has progressed to create common regulatory guidelines (ICH Q8 – 11), it is currently struggling to get to a common understanding of the new vocabulary and integrated systems thinking and actions 11/28/2013

Quality of pharmaceutical products 3 Tablet, capsule, injection, etc. Information, marketing messages, etc. Scientific evidence supporting societal license to market 11/28/2013

Pharmaceutical processes 4 Process for • Developing a product (safety, efficacy, quality) • Manufacturing a product (quality - reproducible and repeatable safety and efficacy profile) • Developing the scientific evidence (safety, efficacy, quality) • Communicating about the product (ensure reproducible and repeatable safety and efficacy profile) 11/28/2013

License to Manufacture and Market 5 Regulatory Authority Manufacturing Market share R&D Revenues Marketing Pre-market review & inspection Post-market review & inspection 11/28/2013

FDA’s Process Validation Guidance 1987 6 Quality can not be tested into products, it has to be built-in by design → Quality by Design Scientific evidence that process is capable of consistently delivering quality products Scientific evidence that product is of acceptable quality 11/28/2013

Quality by Design Vs. Cheating by Design Right first time, ontime review & approval 7 Deliberate adulterated drugs Compliance with cGMP, GLP, GCP,…… GXP Counterfeit and falsified medicines Customer satisfaction with trust & credibility Deliberate false claims 11/28/2013

Companies trying to be on the QbD side… facing challenges • 28 November 2013 • “AAA’s BBB unit gets US FDA import alert” • 4 November 2013 • “XXX promotion of YYY for unapproved uses threatened the most vulnerable populations of our society - children, the elderly and those with developmental disabilities," said Zane Memeger, U.S. Attorney for the Eastern District of Pennsylvania 8 • In 2010 a British drugs giant paid £475million to settle allegations it knowingly made and sold adulterated drugs; agreed to Corporate Integrity Agreement (CIA) • In 2007 a company in New Jersey pleaded guilty to the charge – “Conspiracy to commit an offense against the United States” & “duping the FDA for six years.” 11/28/2013

Quality of the FDA Review & Inspections? US FDA is regarded as the toughest regulatory authority; it takes steps to improve its processes 9 • The PAT Initiative was an attempt to “open the door” significant improvement in multiple functions • PAT Initiative (2001) • CGMP for the 21st Century (2002); Pharmaceutical Quality for the 21st Century (US, EU and Japan via ICH) • Critical Path Initiative (2003) 11/28/2013

Challenges 10 Before the launch of the PAT Initiative • Drug shortages due to manufacturing difficulties • Process deviations coupled with frequent inconclusive investigations • Batch failures and rejections • In-process test debates (e.g., blend uniformity) • Slow and protracted cGMP remediation • Warning Letters, permanent injunctions and consent decree • Multiple review cycles for certain products (e.g., inhalation drugs) • CMC review (and cGMP) harmonization efforts between US, EU and Japan at a impasse on Common Technical Document, Section P2 - ‘Pharmaceutical Development’ 11/28/2013

Internal challenge to FDA staff 11 Questions posed by Dr. Woodcock • “Will this $ x00 million “consent decree” improve quality of the real product? • How effective is “process validation”? Is it not just a “well rehearsed demonstration…. 3 times”? • Is our system truly a “modern quality system”? • Are our “specifications” based on sound science and risk principles? • How is “c” in cGMP established? • Do current regulations support “continuous improvement”? • How efficient is pharmaceutical manufacturing? 11/28/2013

Process understanding is a key to effective control 11/28/2013 12

Powder Blend Uniformity 13 Refers to active ingredient (or preservative) distribution or homogeneity in the “final” blend or mix. • Adequacy of Mixing - satisfactory blending step to assure uniformity and homogeneity [21 Code of Federal Regulation 211.110 (a)(3),1978] 11/28/2013

GMP lessons from a Federal Judge United States of America v. Barr Labs, Inc. 812 F. Supp 458, 3/30/93 • Judge Wolines’ opinion [also] provides scientific and legal guidance to generic and pioneer drug manufacturers about their compliance obligations under the FD&C Act. • Validation studies … and blend uniformity • Test averaging • Retesting • Investigation of batches of failed products • Equipment cleaning and • Record-keeping. 12214.htm The appropriate sample size for Blend Uniformity Analysis (BUA) is, at most, three times the weight of the final dosage unit. 14 • “C” in cGMPs • The sample thief is the state-of-the-art powder sampling technology used by the pharmaceutical industry today for purposes of BUA …. It is prone to sampling error. PDA J Pharm Sci Technol. 1997;51 Suppl 3:i-iii, S1-99 11/28/2013

Struggling with sampling… Stop & go sampling A thief 15 Engineering practice 11/28/2013

The acronym PAT 16 Process Analytical Technology (PAT) Putting analyzers on-line without process understanding would be like “putting ear-rings on a pig” • Process [P] • Analyzer, Analytical…? [A] • Chemistry, System,… Technologies, or Technology? [C, S, or T] Analytical • “….. the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner” Technology (from Greek τέχν η, techne, "art, skill"; and λογία, -logia[1]) • the making, modification, usage, and knowledge of tools, machines, techniques, crafts, systems, and methods of organization, in order to solve a problem, improve a pre-existing solution to a problem, achieve a goal, handle an applied input/output relation or perform a specific function 11/28/2013

PAT definition 17 • “The Agency considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and inprocess materials and processes, with the goal of ensuring final product quality” 11/28/2013

PAT: Validation 18 A focus on process understanding can reduce the burden for validating systems by providing more options for justifying and qualifying systems intended to monitor and control biological, physical, and/or chemical attributes of materials and processes. • In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an online process analyzer and a conventional test method on collected samples may be the only available validation option. In some cases, this approach may be too burdensome and may discourage the use of some new technologies (FDA PAT Guidance 2004) 11/28/2013

Value of ‘Process Understanding” 19 Systems that promote greater product and process understanding can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to demonstrate validation (per 21 CFR 211.100(a), i.e., production and process controls are designed to ensure quality). • In a PAT framework, validation can be demonstrated through continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process end points (FDA PAT Guidance 2004) 11/28/2013

Integrated systems thinking 20 The fast pace of innovation in today's information age necessitates integrated systems thinking for evaluating and timely application of efficient tools and systems that satisfy the needs of patients and the industry. • Many of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner (FDA PAT Guidance 2004) 11/28/2013

Integrated systems thinking at FDA 21 • “Turf” battles to PAT Team Approach • Vocabulary: Negative to Collaborative (“process validation to process understanding”) • “Pharmaceutical Development” information kept at site to shared with CMC reviewers (Quality by Design -ICHQ8) • Risk-based decisions (ICH Q9) • Minimize Prior-Approval Supplements to Change Control within company Quality System (“ICH Q10”) • Reduce regulatory fear to promote continues learning 11/28/2013

PAT Review – Inspection -OPS Team (PATRIOT) Investigators • Robert Coleman (ORA/ATL-DO), Rebeca Rodriguez (ORA/SJN-DO), Erin McCaffery (ORA/NWJ-DO), George Pyramides (PHI-DO), Dennis Guilfoyle (ORA/NERL), Compliance Officers • Albinus D’Sa (CDER), Mike Gavini (CDER), William Bargo (CVM), Brenda Uratani (CDER) Reviewers • Norman Schmuff (CDER), Lorenzo Rocca (CDER) Vibhakar Shah (CDER), Rosario D’Costa (CDER), Raafat Fahmy (CVM), Brian Riley (CDER) 11/28/2013 22

Preparing the regulatory system for globalization PAT ICH Q 8-11 Process Validation 23 FDASIA 11/28/2013

Process Validation keeps the focus on PAT 24 Process validation • Stage 1: Process Design • Stage 2: Process Qualification • Stage 3: Continued Process Verification ASTM • ASTM E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology. • ASTM E2476-09 Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture. • ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices. • ASTM E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. • ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot Acceptance Procedure. 11/28/2013

FDASIA & “adulterated”: What did the Congress intend? 25 11/28/2013

Current state of QbD 26 Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation New Drugs Novice: 22% Pilot: 33% Roll-out: 22% Full implementation: 23% Generics Novice: 40% Pilot: 20% Roll-out: 40% Full implementation: 0% Biologics Novice: 17% Pilot: 67% Roll-out: 17% Full implementation: 0% 11/28/2013

QbD Comments & Challenges 27 Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation Comments “Generics are all about file first and figure out later” “R&D is incentivized on shots on goal not QbD” “We really don’t understand what effects what” “Huge amount of reviewer inconsistency” Challenges (fully implemented) Alignment with 3rd parties Regulators not prepared Current interaction (FDA) not conducive to QbD 11/28/2013

A 10-year research collaboration aimed at transforming pharmaceutical production Novartis – MIT Continuous Manufacturing (started in 2009) November 18, 2011 FDA WL to Sandoz/Novartis: •"Corporate management has the responsibility to ensure the quality, safety, and integrity of its products. Neither upper management at Novartis nor at Sandoz ... ensured global, adequate, or timely resolution of the issues.“ GMP Problems Result in 300 Jobs Chopped At Novartis Plant After Manufacturing Gaffes, Worried Novartis CEO Insists 'Quality Matters’ Novartis CEO Joseph Jimenez ..his company plans to build a commercial-scale continuousmanufacturing facility by 2015 28 “This will change the way medicine is made around the world” 11/28/2013

On-going organization changes at CDER, FDA At FDA, focused attention on changes to ensure a more rational approach to CMC review and cGMP inspections Understand and control sources of variances relevant to quality during development and review process Improved understanding to make risk-based inspections Rational question based review to ensure QbD; science based process validation,… Improve ability to detect “too good to be true data and claims” (protracted detection and correction time) Focus on prevention and reduce reliance on “whistleblowers” and need for DOJ intervention? Additional ‘quality metrics’. 11/28/2013 29

Advice 30 Focus on prevention and reduce reliance on “whistle-blowers” and need for DOJ intervention. Utilize ‘quality metrics 'to gauge performance FDA Rational question based review to ensure QbD; science based process validation,… Pay specific attention to the vocabulary; it can be perceived as a window to your intentions Take proactive steps to prevent catastrophic risks, improve predictability and create competitive advantage by utilizing the principles outlined in the PAT and ICH guidelines Industry Integrative systems approach to decisions by understanding sources of variances relevant to quality Emphasize integrative systems approach to decisions …. Start now, it is a long journey 11/28/2013

A useful document to read 31 • The FDA’s PAT Team and Manufacturing Science Working Group Report • A Summary of Learning, Contributions and Proposed Next Steps for Moving towards the "Desired State" of Pharmaceutical Manufacturing in the 21st Century (2004) • Innovation and Continuous Improvement in Pharmaceutical Manufacturing Pharmaceutical CGMPs for the 21st Century • 11/28/2013

By design; conveys your intention 32 • “The notion ‘by design,’ in the phrase ‘Quality by Design,’ conveys the intention to deliver a product or service with a predefined ‘quality’ so as to satisfy intended customers.” • Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6. 11/28/2013

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