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

a Novartis company

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.

Outline

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

• The FDA Initiative: Vision Vs. Reality• The “desired state”• Journey towards the “desired state”: Where are we today?

A Transforming Agenda


PAT Initiative CGMP InitiativeC

ritical Path Initiative

“Desired State”

20012002

2003


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

http://www.fda.gov/cder/gmp/21stcenturysummary.htm

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


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

http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf


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

The Need for “Vision 2020”

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


Regulatory oversight can be tailored to reflect scientific rigordemonstrated in an application when it is realized through company’s robust quality system

CORRELATIVE KNOWLEDGEWhat Is Correlated to What?

“CAUSAL" KNOWLEDGEWhat “Causes” What?

MECHANISTICKNOWLEDGE

How?

FirstPrinciples Why?

DESCRIPTIVE KNOWLEDGE: What?

Nee

d fo

r reg

ulat

ory

over

sigh

t

Know

ledge based decisions

Desired State

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, scale-up 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 limitedtime)

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

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,…..

How Did FDA Progress the Initiative?


End of PAT – Transformed into QbD


• Distributed “ownership” of the PAT principles for leaders & functions of the regulatory enterprise

• Will this hold?


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

Manufacturing &Manufacturing &Quality AssuranceQuality Assurance

PAT - ICH Q8“Design Space”

DevelopmentDevelopment

Innovation& ContinuousImprovement

Options

Managed underThe Company’sQuality System;

Subject toCGMP Inspections

(no-change or variation)MaintainMaintain

“State of Control”“State of Control”

““Fisher” Fisher” --““ShewartShewart” ” --“Deming”“Deming”Theory of experimental designTheory of experimental designStatistical Process ControlStatistical Process ControlTheory of VariationTheory of Variation


Quality System Requirements QS-9000Third 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 aredefinition corrective actions, not continuous improvement.

• Continuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability and performance.

Is your “cause” special or common?


Stable- Yes; Capable?Unstable

Corrective ActionsEliminate “Special Cause”

Reduce “Common Cause”Variability

Frequent,MajorOOS

Minor,Occasional

OOS

Stable & Capable

On the Continuous Improvement Path

If you can’t measure it, you can’t improve it


© Light Pharma

Process Capability: If you can’t measure it, you can’t improve it

Process Capability Roadmap:

1Has MeasurementSystem capability

been verified?

STOP! Do not compute

Proc. Cap. statistics.Improve the Meas. System.

No

2Is the process stableor unstable via SPC?

YesSTOP!

Do not computeProc. Cap. statistics.

Investigate special causes.Improve process stability.

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

STOP!Transform data.

No4Compute

Cpk

Yes

Unstable

Stable

0Challenge

Specs!

p-value < 0.05p-value > 0.05

Gage R&R& Calibration

SPC Charts

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%”

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

Combined Criteria

21 PAT, cGMP 21st Century / Ajaz Hussain / 10 September 2007PQRI Blend Uniformity Working Group Report

> 40% can be rejected

~ 10% can be rejected“σ < 2”

Other Challenges


Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• IfIf we chose to use a calibrator tablet for a we chose to use a calibrator tablet for a

Gauge R&R study....Gauge R&R study....•• σσ22

(Total for Calib.)(Total for Calib.)•• = = σσ22

(Calib.)(Calib.) + + σσ22C*MeasurementC*Measurement

•• What is the measurement for the Calibrator and what What is the measurement for the Calibrator and what is its variability?is its variability? σσ22

(C*Measurement)(C*Measurement)

•• Since Since σσ22(Calib.)(Calib.) is not known; we have to use is not known; we have to use σσ22

(Total for (Total for Calib.)Calib.)

•• σσ22Total for ProductTotal for Product = = σσ22

ProductProduct + + σσ22Total for Calib.Total for Calib.

Hussain, A.S. Hussain, A.S. BiopharmaceuticsBiopharmaceutics and Drug Product Quality:and Drug Product Quality: Performance Tests Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting"The Science of Quality“. September 26–30, 2004

Other Challenges


Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• Assumption of independent variable?Assumption of independent variable?•• Another aspect Another aspect –– is the measurement capability for a is the measurement capability for a

Calibrator tablet representative of the drug product? Calibrator tablet representative of the drug product? What if there are differences such as disintegration What if there are differences such as disintegration mechanism and buoyancy between the Calibrator and mechanism and buoyancy between the Calibrator and the drug product? the drug product?

Hussain, A.S. Hussain, A.S. BiopharmaceuticsBiopharmaceutics and Drug Product Quality:and Drug Product Quality: Performance Tests Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting"The Science of Quality“. September 26–30, 2004


The Goal and Characteristics of Pharmaceutical Quality Decision System

“The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specificationsapplied to them throughout development and manufacture.”

Characteristics

Goal

Life-cycle

ICH Q6AICH Q6A

What is the ICH Q8, 9, 10 Opportunity?


Specifications

In process controls

Development

Design

Process validation

GMP Controls

ICH Q6A ICH Q6A Decision CharacteristicsDecision Characteristics

“…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.”


Towards a Risk- and Science-Based Approach to Pharmaceutical Quality

Good pharmaceutical

Quality:“an acceptably

low risk of failing to

achieve the desired clinical

attributes”.

Acrobat DocumentSource: Janet Woodcock’s Paper (2004) is attached – click on the Acrobat icon

• 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


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

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 pharmaindustry 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 cost-reduction 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

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

Documents

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