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PAT, cGMP for the 21st Century and ICH Q8, Q9, Q10

PAT, cGMP for the 21st Century and ICH Q8, Q9, Q10

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12/18/2012

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?

2 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

A Transforming Agenda

PAT Initiative
2001

CG M P In
20 02

itiat i ve

itic Cr al th Pa

“Desired State”

itia In e tiv

200 3

3 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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

5 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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 Hussain. FDA Pharmaceutical Inspectorate Training Lecture, August 5, 2004 8 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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? Knowledge based decisions

Need for regulatory oversight

MECHANISTIC KNOWLEDGE How?

Desired State

“CAUSAL" KNOWLEDGE What “Causes” What?

CORRELATIVE KNOWLEDGE What Is Correlated to What?

Current State

DESCRIPTIVE KNOWLEDGE:
What?

9 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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?

13 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

End of PAT – Transformed into QbD
• Distributed “ownership” of the PAT principles for leaders & functions of the regulatory enterprise • Will this hold?

14 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

Opportunity Framework: “Right Specification” to “Continuous Improvement” to “Maximize Efficiency” to “Customer Satisfaction & Profit”
Manufacturing & Quality Assurance

PAT - ICH Q8 “Design Space” Development “Fisher” -“Shewart” -“Deming” Theory of experimental design Statistical Process Control Theory of Variation

Innovation & Continuous Improvement Options Managed under The Company’s Quality System; Subject to CGMP Inspections (no-change or variation)

Maintain “State of Control”

15 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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.

16 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

Is your “cause” special or common?
Corrective Actions Eliminate “Special Cause” Frequent, Major OOS Reduce “Common Cause” On the Continuous Improvement Path Variability Minor, Occasional OOS

Unstable Stable- Yes; Capable?
17 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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:
1 Has Measurement System capability been verified? Yes 2 Is the process stable or unstable via SPC?
Stable

Gage R&R & Calibration

0 Challenge Specs!

No

STOP! Do not compute Proc. Cap. statistics. Improve the Meas. System.

SPC Charts Unstable

STOP! Do not compute Proc. Cap. statistics. Investigate special causes. Improve process stability.

p-value > 0.05

4 Yes Compute Cpk
© Light Pharma

3 Is the data normal “enough” via the Normality Test?

p-value < 0.05

No

STOP! Transform data.

18 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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%”

19 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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

20 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007

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 • Not merely empirically derived from performance of test batches
Source: Janet Woodcock’s Paper (2004) is attached – click on the Acrobat icon
21st Century / Ajaz Hussain / 10 September 2007
Acrobat Document

Good pharmaceutical Quality: “an acceptably low risk of failing to achieve the desired clinical attributes”.

26 PAT, cGMP

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

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