PAT, cGMP for the 21st Century, and ICH Q8, Q9, Q10 Ajaz S. Hussain, Ph.D. Vice President & Global Head Biopharmaceutical Development Sandoz, Inc. 10 September 2007, The British Pharmaceutical Conference 2007, Manchester, UK.
a Novartis company
Outline • The FDA Initiative: Vision Vs. Reality • The “desired state” • Journey towards the “desired state”: Where are we today?
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A Transforming Agenda
PAT Initiative 2001
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“Desired State”
FDA’s Pharmaceutical cGMPs for the 21st Century:Risk-Based Approach • Pharmaceutical manufacturing is evolving from an art form to one that is now science and engineering based. • Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. • Desired future state − Product quality and performance achieved and assured by design of effective and efficient manufacturing processes − Product specifications based on mechanistic understanding of how formulation and process factors impact product performance − Continuous "real time" assurance of quality − Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability − Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product http://www.fda.gov/cder/gmp/21stcenturysummary.htm 4 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Why did FDA launch this initiative? • FDA stands in for the patient/public and must define what constitutes acceptable quality • During the 1999 – 2003 period FDA had to reexamine its definition of quality − Recurring OOS, Warning Letters, Consent Decree’s − Drug Shortages and safety related issues − Increasing complexity of products, lacking ability to approve complex generics, etc. − Slow innovation and continuous improvement − High cost of manufacturing
Source:
The PAT Team and Manufacturing Science Working Group Report: Acrobat Document
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Example: An Validated Process – Could not be manufactured reliably: Did the FDA ask the “right” questions?
A potent narcotic analgesic solid oral dosage form – FDA Warning Letter
http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf 6 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Real & Surrogate Customers: Are the “two products” aligned? • FDA leaders posed the question (to staff) - What is Quality? − Different (CMC Vs. GMP) interpretation within FDA (and industry); but primarily focused on “complying with Specs - CGMP’s” − “C” in CGMP’s based on inspectional findings; not via a science based process − CGMP’s established 25 years ago! − “Validated” processes – recurring manufacturing difficulties. Why? − Are we focusing on the “right” product? • Quality of Documentation- Quality of (real) Products 7 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
The Need for “Vision 2020”
Source: Ajaz FDA Pharmaceutical Training Lecture, August 5, 2004 8 PAT, cGMP 21st Hussain. Century / Ajaz Hussain / 10 September Inspectorate 2007
Knowledge based decisions
Need for regulatory oversight
Regulatory oversight can be tailored to reflect scientific rigor demonstrated in an application when it is realized through company’s robust quality system First Principles Why?
MECHANISTIC KNOWLEDGE How?
Desired State
“CAUSAL" KNOWLEDGE What “Causes” What?
CORRELATIVE KNOWLEDGE What Is Correlated to What?
DESCRIPTIVE KNOWLEDGE:
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What?
Current State
Specific opportunities (but only under PAT/QbD system) • Regulatory flexibility − Risk based inspections (when site is considered to be “low risk”) − Post approval changes without “prior approval supplements” − Increased opportunities for post approval biowaivers − Increased likelihood of acceptance of scientific justification (deviation investigations, number of conformance batches, scaleup criteria, etc.) − Opportunity to justify rational regulatory specifications − Opportunity to seek alternate regulatory pathway for approval of complex generic products (in US) − Opportunity to avoid the review back-log and enhanced opportunity for regulatory communication (in US; but for limited time) 10 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Specific opportunities (but only under PAT/QbD system) • Continuous improvement − Eliminate recalls, deviations, investigations − Improve yield − Cycle time reduction − Maximize Stock Turn − Other “lean metrics” • Development – right first time − Leveraging prior knowledge − Reducing development time & cost (over time; after initial investment) • Leaving competition behind − Continuous manufacturing; small footprint − Real time release 11 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Challenges • Regulatory uncertainty − Will the initiatives be fully implemented? − Will the implementation be harmonized across ICH regions? − Will regional regulatory authorities adopt these principles? − How should regulatory submissions be modified to incorporate the new concepts? • Organizational divide − Different levels of understanding of the concepts − Past experience and culture − Performance metrics narrowly focused • Training and inter-disciplinary communication − Multivariate statistics, engineering, material science,….. 12 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
How Did FDA Progress the Initiative?
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End of PAT – Transformed into QbD • Distributed “ownership” of the PAT principles for leaders & functions of the regulatory enterprise • Will this hold?
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Opportunity Framework: “Right Specification” to “Continuous Improvement” to “Maximize Efficiency” to “Customer Satisfaction & Profit” Manufacturing & Quality Assurance
Innovation & Continuous Improvement Options
PAT - ICH Q8 “Design Space” Development “Fisher” -“Shewart” -“Deming” Theory of experimental design Statistical Process Control Theory of Variation
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Maintain “State of Control”
Managed under The Company’s Quality System; Subject to CGMP Inspections (no-change or variation)
Quality System Requirements QS-9000 Third Edition element 4.2.5—Continuous Improvement (1998). • For those product characteristics and process parameters that can be evaluated using variable data, continuous improvement means optimizing the characteristics and parameters at a target value and reducing variation around the value. • For those product characteristics and process parameters that can only be evaluated using attribute data, continuous improvement is not possible until characteristics are conforming. • If attribute data results do not equal zero defects, it is by definition nonconforming product. Improvements made in these situations are definition corrective actions, not continuous improvement. • Continuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability and performance.
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Is your “cause” special or common? Corrective Actions Eliminate “Special Cause”
Reduce “Common Cause” On the Continuous Improvement Path Variability
Frequent, Major OOS
Unstable Stable- Yes; Capable? 17 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Minor, Occasional OOS
Stable & Capable
If you can’t measure it, you can’t improve it Process Capability: If you can’t measure it, you can’t improve it
Process Capability Roadmap:
0 Challenge Specs!
1 Has Measurement System capability been verified? Yes 2 Is the process stable or unstable via SPC?
p-value > 0.05
4 Yes Compute Cpk
Gage R&R & Calibration
No
SPC Charts Unstable
STOP! Do not compute Proc. Cap. statistics. Improve the Meas. System.
STOP! Do not compute Proc. Cap. statistics. Investigate special causes. Improve process stability.
Stable
3 Is the data normal “enough” via the Normality Test?
© Light Pharma
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p-value < 0.05
No
STOP! Transform data.
Pharmaceutical “Customer” Specifications • Often combine attribute (no unit outside..) and continuous variable (RSD) in quality decision process • For example: Dose Content Uniformity
− Upper Specification Limit = 125% − Lower Specification Limit = 75% − Standard Deviation not to exceed 7.8% − Test sample size 30 − “No unit in 30 is outside 75-125%”
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Process Capability and Variability • Without the “attribute” criterion − Assuming a stable process; normal distribution − Mean = 100%, %RSD = 7.8%, n=30
• Cp=Cpk = 1.07 and • ~ “3σ” process − Standard Deviation = 2.0%
• Cp=Cpk = 4.17 • >”6σ” process
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Combined Criteria
~ 10% can be rejected “σ < 2” > 40% can be rejected
PQRI Blend Uniformity Working Group Report 21 PAT, cGMP
21st
Century / Ajaz Hussain / 10 September 2007
Other Challenges Difficult questions faced by Manufacturing Groups and Regulators… • If we chose to use a calibrator tablet for a Gauge R&R study....
• σ2(Total for Calib.)
• = σ2(Calib.) + σ2C*Measurement
• What is the measurement for the Calibrator and what is its variability? σ2(C*Measurement) • Since σ2(Calib.) is not known; we have to use σ2(Total for Calib.)
• σ2Total for Product = σ2Product + σ2Total for Calib. Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004 22 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Other Challenges Difficult questions faced by Manufacturing Groups and Regulators… • Assumption of independent variable? • Another aspect – is the measurement capability for a
Calibrator tablet representative of the drug product? What if there are differences such as disintegration mechanism and buoyancy between the Calibrator and the drug product?
Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004 23 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
The Goal and Characteristics of Pharmaceutical Quality Decision System Goal
“The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.” Characteristics Life-cycle
ICH Q6A 24 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
What is the ICH Q8, 9, 10 Opportunity? ICH Q6A Decision Characteristics Specifications In process controls Development Design Process validation GMP Controls “…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.” 25 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Towards a Risk- and Science-Based Approach to Pharmaceutical Quality • For mass-produced pharmaceuticals, statements about quality must be probabilistic − Risk (probability of harm * severity of harm) connects desired clinical attributes – clinical performance as labeled, absence of contamination, and availability – to attributes measurable during production − What is the link between measurement and risk? Quality by Design • Product and process performance characteristics are scientifically designed to meet specific objectives
Good pharmaceutical Quality: “an acceptably low risk of failing to achieve the desired clinical attributes”.
• Not merely empirically derived from performance of test batches Source:
Janet Woodcock’s Paper (2004) is attached – click on the Acrobat icon
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Acrobat Document
The “desired state” is a continual journey to improve… Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance An ability to effect continuous improvement and continuous "real time" assurance of quality 27 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
Develop effective CAPA – eliminate “special cause” variability Utilize Process capability analysis – reduce/control “common cause” variability Identify, understand and acquire ability to predict critical to quality attributes of materials (CQA) (product/process/measurement) Focus on the “critical few” Establish CQA target values and acceptable variability around the target value Utilize a monitoring system that demonstrates “state of control” preferably based on critical material attributes (not just end product testing)
An Perspective on Pharmaceutical Process Efficiency: Early signs that a few companies can take the lead….. “Although there's been plenty of interest in process improvement in the pharma industry in recent years, the methodology's history with the industry is still very new. Profit margins have declined in recent years, but they're still much larger than in other industries, a sign that the industry could still slip in its newfound dedication to urgent costreduction methodologies. Whether the industry is serious about quality is still unclear, though there have been early signs that a few companies can take the lead and show their competitors how to trim the proverbial fat and succeed in a new pharmaceutical market.” L. Smith, Quality Digest, September 9, 2007
http://www.qualitydigest.com/mar06/articles/01_article.shtml 28 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007
