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Moving Towards the “Desired State”: Scientific Gap Analysis. Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA 20 October 2004, ACPS Meeting. Good Pharmaceutical Quality – an acceptably low risk of failing to achieve the derived clinical attributes.

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Moving towards the desired state scientific gap analysis

Moving Towards the “Desired State”: Scientific Gap Analysis

Ajaz S. Hussain, Ph.D.

Deputy Director, Office of Pharmaceutical Science, CDER, FDA

20 October 2004, ACPS Meeting


Good Pharmaceutical Quality – an acceptably low risk of failing to achieve the derived clinical attributes

Janet Woodcock, MD

Acting Deputy Commissioner for Operations

October 6, 2004


How do we link measurement and risk
How Do We Link Measurement and Risk? failing to achieve the derived clinical attributes

  • Quality by Design (QbD)

  • Derive multivariate model during development

  • Confirm during clinical phase

Janet Woodcock, MD

Acting Deputy Commissioner for Operations

October 6, 2004


Quality system
Quality System failing to achieve the derived clinical attributes

  • Final link between product and customer-driven quality attributes

  • Integrate product & process knowledge on ongoing basis

  • Assure ongoing control

  • Enable continuous improvement

Janet Woodcock, MD

Acting Deputy Commissioner for Operations

October 6, 2004


Summary
Summary failing to achieve the derived clinical attributes

  • Future definitions of quality should be probabilistic in nature

  • Science management, risk-management and quality management are important

  • FDA must be leaders in this arena

Janet Woodcock, MD

Acting Deputy Commissioner for Operations

October 6, 2004


Horizontal systems view
Horizontal (Systems) View failing to achieve the derived clinical attributes

R&D

Manufacturing

Review

Inspection

Quality of the interface between functional units determines

the effectiveness and efficiency of the process

The interface can be “handoffs between functions” and often

is in need for better coordination

Rapid and broad movement of information and knowledge sharing

is necessary for process optimization

From “Technology Transfer” to “Knowledge Transfer”


http://amptiac.alionscience.com/pdf/2001MaterialEase13.pdf failing to achieve the derived clinical attributes


Current state
Current State failing to achieve the derived clinical attributes

  • Today C,M,C Design information available in applications is limited and varied

  • High degree of uncertainty

    • Critical variables and process controls

    • Process validation

    • Focus on in-process and product testing

    • Risk coverage post approval

    • Supplements are a means for risk mitigation

  • Traditional use of “market standards” as release tests – not very effective for process understanding and continuous improvement

  • Variable test methods for physical characteristics

  • Less than optimal “systems” perspective and approach

  • Low efficiency and high cost of drug development and manufacturing

  • Continuous improvement is difficult (or not possible)



Information and knowledge for regulatory assessment decision process
Information and Knowledge for Regulatory Assessment & Decision Process

  • Quality & Performance - Design relationships

    • Impact of formulation & process factors on performance

  • Specifications based on “mechanistic” understanding

  • Ability to effect continuous improvement

  • Continuous “real time” quality assurance


Design process
Design Process Decision Process

  • Design is about doing things consciously, and not because they have always been done in a certain way

  • It is about comparing alternatives to select the best possible solution

  • It is about exploring and experimenting in a structured way

http://www.designcouncil.org.uk


Design is about doing things consciously

Intended Use Decision Process

Route of administration

Patient population

…..

Product Design

Design Specifications

(Customer requirements)

Manufacturing Process

Design and Control

Design is about doing things consciously

Product

Performance:

Design specifications

reliably and consistently

deliver the therapeutic

objectives

Capability

Ability to reliably and

consistently

deliver the target

product design

specifications


Ich q8 ctd q p2

Drug Substance Decision Process

or API

Intended Use

Route of administration

Patient population

…..

Product Design

P2.1 and 2.6

Components of drug product

P2.2, 2.4, 2.5, 2.6

Drug Product

Container Closure System

Microbiological Attributes

Compatibility (e.g., recon)

Design Specifications

(Customer requirements)

P2.3

Manufacturing Process Development

Manufacturing Process

ICH Q8: CTD-Q (P2)


Design thinking
Design Thinking Decision Process

  • Design thinking makes the user paramount, ensuring that the services we end up will do the job they're supposed to as well as delighting the customer

  • Design thinking and methods provide new routes to better public services that meet people's needs and deliver value for money.

http://www.designcouncil.org.uk


Quality performance design relationships
Quality & Performance - Design relationships Decision Process

  • Conventional vs Novel Design

    • Utility of prior knowledge

      • From similar drug products

      • Pharmaceutical development information on prototypes and selected novel design

    • “Level” of mechanistic understanding

      • Pre-formulation program

        • Mechanism of degradation

        • Mechanism of absorption; BCS Class

        • Physical characterization

    • Ability to reliably predict performance – confirm as you progress (e.g., scale-up,…) - Design of development protocol


Quality performance design relationships1
Quality & Performance - Design relationships Decision Process

  • Level of understanding increases over time

    • Structured empirical approach

    • Use of prior knowledge to identify and select a design space for characterization

      • For example; Failure Mode Effect Analysis

      • Initial conditions for screening experiments

      • Characterization and modeling experiments (including – interactions)

    • Impact of formulation & process factors on performance

      • Design of clinical trial material and clinical trial information

      • Shelf-life



Robust design after taguchi
Robust Design (after Taguchi) Decision Process

Principle – improving the quality of a product by minimizing the effects of variation without eliminating the causes.

Robust design has become one of the powerful tools to assist designers to make reliable decisions under uncertainty.

Phadke, M.S., Quality Engineering using Robust

Design. Prentice Hall, Englewood, New Jersey, 1989

Du, X. and Chen, W. Methodology for managing

Effect of uncertainty in simulation-based systems

Design. AIAA J 38: 1471 (2000).


Performance of a solids processing units aiche journal 47 107 125 2001
Performance of a Solids Processing Units Decision ProcessAIChE Journal 47: 107-125 (2001)

Performance

of a Unit

Bulk Mechanical

Properties

Angle of repose

Unconfined yield stress

Forces Acting

on Particles

Adhesion forces

Impact forces

Material

Characteristics

Hamaker constant

Dielectric constant

Young’s modulus

Particle

Attributes

PSD

Shape

Composition

Equipment

Design

Geometry

Constituent parts

Material properties

Operating

Conditions

Speed of moving parts

Temperature

Humidity


ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA Decision ProcessFOR DRUG PRODUCT DISSOLUTION

What specific test conditions and acceptance criteria are appropriate? [IR]

How?

What?

YES

Develop test conditions and acceptance

distinguish batches with unacceptable BA

dissolution significantlyaffect BA?

NO

Do changes informulation ormanufacturing variables affect dissolution?

Are these changes controlledby another procedure

and acceptancecriterion?

YES

Why?

YES

Why?

NO

NO

Adopt appropriate test conditionsand acceptance criteria without

regard to discriminating power, to

pass clinically acceptable batches.

Adopt test conditions and acceptance

criteria which can distinguish

these changes. Generally, single point

acceptance criteria are acceptable.

Why?

How do we currently establish dissolution specifications

aaps Annual Meeting


ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA Decision ProcessFOR DRUG PRODUCT DISSOLUTION

What specific test conditions and acceptance criteria are appropriate? [IR]

Clin. Pharm.

What?

Product

Design

(Postulate -

Confirmed

Based on mechanism

and/or empirically)

YES

Develop test conditions and acceptance

distinguish batches with unacceptable BA

dissolution significantlyaffect BA?

Design of

Manufacturing

and Controls

How (reliable)?

NO

Do changes informulation ormanufacturing variables affect dissolution?

Are these changes controlledby another procedure

and acceptancecriterion?

YES

So what?

Overall Risk-based

CMC:Why?

YES

NO

NO

Adopt appropriate test conditionsand acceptance criteria without

regard to discriminating power, to

pass clinically acceptable batches.

Adopt test conditions and acceptance

criteria which can distinguish

these changes. Generally, single point

acceptance criteria are acceptable.

Overall CMC Systems approach (e.g., link to morphic form,

particle size, stability failure mechanisms) CMC:Why? Then How?

aaps Annual Meeting


Static manufacturing
Static Manufacturing Decision Process

“Within”

(Change

Target setting)

“Outside”


Making and reporting manufacturing changes current regulations
Making and Reporting Manufacturing Changes: Current Regulations

  • Section 506A of the Act and § 314.70 provide for four reporting categories based on

    • “……potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.”

      • “Substantial” potential- Major change – Prior Approval Supplement

      • “Moderate” potential - Moderate change - Changes Being Effected in 30 Days or Changes Being Effected

      • “Minimal” potential – Minor change -Annual Report

  • No change – no reporting - “beyond the variation already provided for in the application.”

“Connection

To Risk”


Design space f intended use design control risk

Assessment Regulations

Based on ICH Q8

Information/Knowledge

Quality System

Risk Classification

Process Design

& Control

Specifications

Product Design

Intended Use

ICH Q9

Risk Tools

Reliability

To Deliver

Design

Requirements

Design

Requirements

“Design Space” = f (Intended Use * Design * Control * Risk)


Pharmaceutical quality system
Pharmaceutical Quality System Regulations

PAC

Drug Safety

Process Capability

Continuous Learning

and Improvement

Clinical

CGMPs

Clin Pharm & Bio

Controls

CGMP “Design &

Knowledge Space”

Pharm/Tox

Clinical “Design

& Knowledge Space”

Chemistry

Manufacturing

CMC “Design and Knowledge Space”


Cgmp initiative

"Prove it" Regulations

"Improve it“

Continuous Improvement

Innovation

"Unable to prove"

Why?

"Corrective and Preventive Actions"

"Do what you say"

"Say what you do"

CGMP Initiative

http://www.fda.gov/cder/gmp/index.htm

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


Frontiers in chemical pharmaceutical engineering
Frontiers in Chemical [& Pharmaceutical] Engineering Regulations

Systems Engineering

2000 – : Molecular

Transformations, Multi-Scale

Analysis, Systems view

Chemical Engineering

ChE Science

1965 – Transport phenomena,

Process dynamics, Process Engineering,

Computer Technology

1955 - Applied Kinetics & Process Design

1945 - ChE Thermodynamics & Process Control

Unit Ops

1935 - Material & Energy Balances

Pharmaceutical Engineering

1925: Unit Operations

1905-1915: Industrial Chemistry

1960’s Industrial Pharmacy

Brian Scarlett 2001 and http://mit.edu/che-curriculum/2003/index.html


Systems engineering quality systems

Draft Guidance for Industry Regulations

Quality Systems Approach to Pharmaceutical

Current Good Manufacturing Practice Regulations

Production

S y s t e m

http://www.fda.gov/cder/guidance/6452dft.doc

Facilities &

Equipment

S y s t e m

Quality System

Packaging &

L a b e l i n g

S y s t e m

M a t e r i a l s

S y s t e m

Laboratory

Controls

System

Systems Engineering – Quality Systems

Traditional goals

Non-traditional goals

(risk based, flexibility, robustness, scalability, continuous improvement, innovation,

efficiency,….)

Characteristics

Complexity, uncertainty

Relationships (between goals & characteristics)

Knowledge and information centric relationships

Fundamental issues


Managing professional intellect
Managing Professional Intellect Regulations

  • A corporation’s success today lies more in its intellectual and system capabilities than in its physical assets

    • Cognitive knowledge (know-what)

    • Advanced skills (know-how)

    • System understanding (know-why)

    • Self-motivated creativity (care-why)

Increasing

Value

Quinn, Anderson, and Finkelstein. HBR, April 1996


Managing professional intellect1

Quinn, Anderson, and Finkelstein. HBR, April 1996 Regulations

Managing Professional Intellect

  • Recruit the best

  • Force intensive early development

  • Constantly increase professional challenge

  • Evaluate and weed

  • Capturing knowledge in systems

  • Overcome professionals’ reluctance to share information

  • Organize around intellect


Immediate educational needs
Immediate Educational Needs Regulations

  • Introduction to statistical quality control

    • And not a “biostatistics”

  • Understanding variability

  • Molecular pharmaceutics and biopharmaceutics

  • Engineering principles

  • Risk assessment and communication

  • Systems approaches and thinking

    • Intro to Deming and others

  • Team building and communication


“Coming together is a beginning….. Regulations

Keeping together is progress….

Working together is a success……”

--- Henry Ford


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