Published on January 8, 2014
Pinch-hitting @ The University of Heidelberg QbD / PAT Conference 2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 10/16/2013 AJAZ@AJAZHUSSAIN.COM 1
Two talks you were expecting • What to expect in the next 25 years of medicine? Dr Janet Woodcock, Director CDER, FDA, USA 10/16/2013 • The Role and Relationship of CGMP Statistics with Pharmaceutical Quality • Recent enforcement action examples • CGMP statistical references • Use of Consensus Standards for Pharmaceutical • Manufacturing quality Dr Karthik Iyer FDA /CDER AJAZ@AJAZHUSSAIN.COM 2
"It is always a wild ride, but it's always interesting" Continuous manufacturing Molecular medicine Political turmoil Drug regulation will grow less intrusive and less complex EHRs will finally be standard http://www.fiercepharma.com/story/fdas-woodcock-what-expect-next-25-years-medicine/2011-10-23 10/16/2013 AJAZ@AJAZHUSSAIN.COM 3
“…I am not planning to retire as erroneously reported…” "I want to assure you that I am not planning to retire as erroneously reported in the media today," she said. "In fact, quite the opposite is true. I am becoming more deeply involved in many of the Center’s issues, including the proposed reorganizations of the Office of Pharmaceutical Quality (OPQ) and the Office of Generic Drugs (OGD)." 10/16/2013 AJAZ@AJAZHUSSAIN.COM 4
Shifting the way FDA operates…. Vision 2020- I can see clearly now Globalization requires fundamental shift in the way FDA operates Establishment of foreign offices Quality & performance by design + Continuous “real time” monitoring of quality Increased foreign inspections Specifications based on mechanistic understanding of how formulation and process factors impact product performance Risk-based monitoring and inspections Global collaborations to harmonize standards and leverage resources High efficiency and capacity utilization Investing to strengthen regulatory systems abroad Efforts to combat counterfeit and substandard drugs “Real time” review and inspection from Rockville, White Oak, NJDO,... 10/16/2013 Implementation of legislative mandates (FDASIA) AJAZ@AJAZHUSSAIN.COM 5
A decade ago Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach Final Report - Fall 2004 Department of Health and Human Services, U.S. Food and Drug Administration September 2004 This Report is also available in PDF (214KB) 3 September 2003 10/16/2013 AJAZ@AJAZHUSSAIN.COM 6
Comments & challenges Challenges Comments (fully implemented) “Generics are all about file first and figure out later” Alignment with 3rd parties “R&D is incentivized on shots on goal not QbD” Regulators not prepared “We really don’t understand what effects what” Current interaction (FDA) not conducive to QbD “Huge amount of reviewer inconsistency” Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation 10/16/2013 AJAZ@AJAZHUSSAIN.COM 7
CGMP Statistics and Pharmaceutical Quality 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. 10/16/2013 AJAZ@AJAZHUSSAIN.COM 8
Risk-based monitoring & inspections PAT 10/16/2013 ICH Q 8-11 Process Validation AJAZ@AJAZHUSSAIN.COM FDAISA 9
FDA expects more statistical thinking in validation A high percent of the population is within specification Provide statistical confidence that… A population parameter is within specification - Mean; Standard Deviation; RSD; Cpk/Ppk A standard test (UDU, Dissolution, etc.) will pass 10/16/2013 AJAZ@AJAZHUSSAIN.COM 10
Enforcement actions Statistical confidence Control of suppliers 10/16/2013 Root cause investigations Data integrity AJAZ@AJAZHUSSAIN.COM 11
ASTM E2709 Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure Sample Size Effect on RSD Limit @ 95% Confidence / 95% Probability Sample Size Effect on RSD Limit @ 99% Confidence / 95% Probability 7.00 7.00 6.00 6.00 n=10 5.00 5.00 n=10 4.00 n=30 n=100 3.00 RSD RSD n=20 n=20 4.00 n=30 n=100 3.00 n=500 2.00 n=1000 n=500 2.00 1.00 1.00 0.00 n=1000 0.00 85.1 87.5 90 92.5 95 97.5 100 102.5 105 107.5 110 112.5 85.1 114.9 87.5 90 92.5 95 97.5 100 102.5 105 107.5 110 112.5 114.9 Sample Mean Sample Mean Karthik Iyer 10/16/2013 AJAZ@AJAZHUSSAIN.COM 12
ASTM E2334: Setting an Upper Confidence Bound For a Fraction or Number of NonConforming items, or a Rate of Occurrence for Nonconformities, Using Attribute Data, When There is a Zero Response in the Sample Confidence vs Sample Size 100 90 80 Confidence 70 60 Pd=1% 50 Pd=0.5% 40 Pd=0.065% 30 20 10 0 6 10 12 24 30 100 150 300 500 1000 Sample Size Karthik Iyer 10/16/2013 AJAZ@AJAZHUSSAIN.COM 13
Sampling plan, capability, stability Capability Stability 10/16/2013 • Can the system consistently make product that meets specifications? • The demonstrated CPK ensures that Critical Quality Attributes (CQAs) are consistently met • The CPK meets requirements of other steps in the process, particularly for in process data • Can the system consistently make product that meets specifications? • Does the system ensure consistent product, even with varying inputs? • Common cause variation or special cause variation? AJAZ@AJAZHUSSAIN.COM 14
Common Investigation-Related Findings Failure/OOS SOPs usually good, but not followed OOS’s are tested into compliance Complaints not substantively investigated Adverse complaint trend not detected or investigated Scope of Investigations (see 211.192): isolated issue or recurring? Appropriate expertise (SMEs) to investigate/diagnose/correct Rick Friedman 10/16/2013 AJAZ@AJAZHUSSAIN.COM 15
Every batch, Every day… We rely upon the manufacturing controls and standards to ensure that time and time again, lot after lot, year after year the same clinical profile will be delivered because the product will be the same in its quality…” Janet Woodcock 10/16/2013 AJAZ@AJAZHUSSAIN.COM 16
FDA CDER Warning Letters 2011-2013 2011 2012 (August) 2013 UK Jamica Germany Mexico Switzerland Canada Denmark Australia Spain Japan Italy China Poland Thaiwan Israel India 10/16/2013 UAE AJAZ@AJAZHUSSAIN.COM 17
Selected media clips “FDA Cracks Down on Indian Manufacturers, Citing New FDASIA Authority and Egregious Violations” http://www.raps.org/focus-online/news/news-article-view/article/3837.aspx 10/16/2013 “FDA Data Integrity Concerns Continue in India as Three More Firms Draw GMP Warning Letters” “if that is because there are more data integrity problems or if we are getting better at finding them – or a little bit of both.” http://www.ipqpubs.com/news/ AJAZ@AJAZHUSSAIN.COM 18
Reasons for concern Egregious violations noted and increasing frequency and rigor of inspections Gaps in understanding and in effective communication Behaviors - outcome based; how you get there not aligned with subtleties of GXP Decreased risk tolerance going forward Many changes in the US regulatory and legal landscape Key challenges are people issues; solutions need to be across the enterprise 10/16/2013 AJAZ@AJAZHUSSAIN.COM 19
Distinguishing between cognitive biases & cheating by design Ability to distinguish - critical to business continuity 10/16/2013 Ability to distinguish - a competitive advantage AJAZ@AJAZHUSSAIN.COM 20
Human Factors Analysis and Classification System for CGMPs Organizational Influences Latent Conditions Failure in Supervision Latent Conditions Preconditions for Deviations Latent Conditions Deviations Reason, J. Human Error, New York, and Cambridge: Cambridge University Press, 1990 Failed or Absent Controls 10/16/2013 Active Conditions Shappell, S. A. and Wiegmann, D. A. "The Human Factors Analysis and Classification System -HFACS." Washington: US Department of Transportation, Federal Aviation Administration, Office of Aviation Medicine, 2000. AJAZ@AJAZHUSSAIN.COM 21
Steps to improve patient protection in the US* Decreased risk tolerance US regulatory landscape People issues • In US serious quality issues noted in both imported and domestic supplies • Control of imports more difficult; higher concern • Detections and resolution not optimal • Confidence reduced in the System • FDA authority increased under FDASIA • cGMP definition expanded • User fees • Review changes • Types and capacity of inspections increased • FDA India • cGMP violations & False Claims Act • Counterfeits, adulteration • Adulteration in the US points to intention इरादा (document what you do and do what you document) • Current system heavy on SOP’s –easy to say ‘Great Mounds of Paper’ • With FDA’s encouragement a new paradigm in manufacturing is visible *Similar efforts globally; although not discussed in the presentation these are considered 10/16/2013 AJAZ@AJAZHUSSAIN.COM 22
Changes at FDA CDER…… 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 10/16/2013 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 “whistle-blowers” and need for DOJ intervention? Additional ‘quality metrics’. AJAZ@AJAZHUSSAIN.COM 23
10/16/2013 • “FDA’s goals in India .. better and more robust information to help FDA officials in the various FDA headquarter Offices… at the borders make better decisions about the products from India ..developed for the U.S. market.” (FDA website) • Focused and frequent inspections • Whistleblowers encouraged • Manufacturing metrics? “too good to be true” • Rigorous question based review and alignment between review and compliance functions By 2020: Market-manufacturing dynamics to shift significantly 2014 – : FDA’s ability to detect will increase rapidly Consider the following AJAZ@AJAZHUSSAIN.COM • Novartis CEO Joseph Jimenez -company plans to build a commercial-scale continuous-manufacturing facility by 2015 (MIT Technology Review November 6, 2012) • UK pushes continuous manufacturing (March 24, 2011) • PAT, QbD spur continuous processing (April 5, 2011) • Sanofi's Genzyme looking hard at continuous manufacturing (January 31, 2013) • GSK commits to continuous processing (February 19, 2013) FiercePharma Manufacturing 24
Prevention: Why, How & What? What are the gaps? • People • Process • Information & Technology FDA Inspection • Triggers of 483, import alert & WL • Impact and CAPA • Management actions expected Why Responsibility 10/16/2013 Consent decree • Corporate Integrity Agreements • Independent review • Etc.. How 1. 2. 3. 4. Gap analysis Clear message -what is not acceptable Correction & improvement plan Sustainability: strengthen quality, policy, Mgmt. oversight, organization, people, process, technology AJAZ@AJAZHUSSAIN.COM What 1. 2. 3. Inspection ready – any day Lower risk-profile (decreased frequency of 483, and inspections) Right first time and on-time approvals 25
Are we at a tipping point? 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.“ Novartis CEO Joseph Jimenez ..his company plans to build a commercialscale continuousmanufacturing facility by 2015 GMP Problems Result in 300 Jobs Chopped At Novartis Plant “This will change the way medicine is made around the world” After Manufacturing Gaffes, Worried Novartis CEO Insists 'Quality Matters’ http://www.technologyreview.com/view/427895/the-future-of-pharma-is-incredibly-fast/ 10/16/2013 AJAZ@AJAZHUSSAIN.COM 26
Are we at a tipping point? Eli Lilly • plans to have installed and demonstrated four separate continuous processing platforms by early next year. GSK • "We’ve started to deploy the first production versions in UK factories," Witty told investors. • Invest $50 million to install and validate commercial-scale continuous processing equipment at a plant in Singapore Pfizer The PROMIS Centre • Already evolved towards a hybrid model between continuous and batch processing, with continuous approaches in areas such as coating and crystallization sitting alongside traditional batch systems • officially launched on 19 February 2013 to provide R&D on the use of continuous processing of solid dosage form pharmaceuticals http://www.pharmafile.com/news/181079/pharma-makes-progress-continuous-processing 10/16/2013 AJAZ@AJAZHUSSAIN.COM 27
Self- detection, correction, prevention and improvement is required, expected and encouraged GXP Puzzle to Performance Guiding principles 1. Protect patients 2. Protect shareholder value 3. Competitive advantage 10/16/2013 • What if we find something objectionable? • A common concern • Correction and prevention the best option • Structured program • Regulatory strategies for improvement, inspection, and submission • Confidence in data for sound decision making • Risk-based impact assessments and specific steps to strengthen GXP systems and improved process understanding and controls • Improving product development to address evolving requremtns of QbD • People development through training and mentoring • Corporate Voice for Quality - optimal management oversight via effective business process analytics and controls pertaining to quality of products (pharmaceutical and documents) AJAZ@AJAZHUSSAIN.COM 28
What will be your strategic response? Detect, Correct, Prevent and/or Improve Remediation after an FDA 483, Import Alert or WL Customer focused Customer focus questionable Positive environment Negative environment Competitive advantage Loss of shareholder value 10/16/2013 AJAZ@AJAZHUSSAIN.COM 29
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