Process Analytical Technology:

Neue Trends in der Pharmaceutischen Industrie

Dr. Fritz ErniNOVARTIS Pharma

Global Quality Operations

CH-4002 Basel, Switzerland

Fritz Erni2

Outline The Vision of the desired state What is PAT and QbD ICH Q8 is a Door Opener for

Describing Quality by Design Including more Science and Risk

Management Introduces the Concept of Design Space Design Space Concept for Analytical

Methods Summary

Fritz Erni

Global Challenges

• Rising Global Regulatory Bar• Consent decrees and enormous fines from

manufacturing compliance deficiencies• Higher safety hurdles for marketing approval• Challenge of Sustaining Product Pipeline &

Flow• Biotech contribution less than expected• Government price control• Challenge of Earning Stakeholders Trust

Fritz Erni

“A Paradigm in Crisis”

Main points from this:

• High tech in R & D

• Relatively low tech in Manufacturing

• It matters

Big Pharma manufacturing costs are $ 90 Bn

Significantly more than R&D

Quality by Design: A Challenge to the Pharma Industry

(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

Fritz Erni

PAT in the Wall Street Journal Europe 3.9.03

•FDA Commissioner Mark McClellan :

... You need to improve!

... has room for improvements:Semiconductor industry 1 ppm defectsPharmaceutical industry 5 to 10%

.. Acknowledging the FDA role in inhibiting changes ...

•WSJE on the Lauch of the FDA PAT guideline:

Fritz Erni

Impact Process Capability

Process Capability

2 σ 3 σ 4 σ 5 σ 6 σ

Rejected Batches

31.9 %6.7 %0.7 %1 %o10 ppm

Fritz Erni

Process Understanding

•Pharma •Air Plane

Fritz Erni

Typical Ingredients of a Tablet

Active 5µm

Corn Starch 30µm

Lactose 100µm

MicrocrystallineCellulose 102100µm

Dr. Susanne Keitel

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Industry’s Vision to be achieved in 2-5 years

• A single global harmonized:A single global harmonized:− Drug Quality StandardDrug Quality Standard– Interpretation of the Drug Quality StandardInterpretation of the Drug Quality Standard

• A Drug Quality Standard based on:A Drug Quality Standard based on:– Risk ManagementRisk Management– ScienceScience

• Mutual recognition of:Mutual recognition of:– “ “equivalent” quality system evaluationsequivalent” quality system evaluations– CMC review and approval CMC review and approval – Across all 3 regions.Across all 3 regions.

Brussels July 2003

Fritz Erni

Desired 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

• An ability to effect Continuous Improvement and Continuous "real time" assurance of quality

Fritz Erni

2004

2005

2006

FDA PAT guideline

FDA DraftQuality Systems

FDA : Innovation and ContinuousImprovement in

Pharmaceutical Manufacturing

FDA Pharmaceutical cGMP for the 21st Century – a Risk based Approach

GMP and Regulatory Actions

Expert Working Groups (EWG)ICH

Q8Pharmaceutical Development

Q9Risk Management

Q10 Pharmaceutical Quality System

Update Q6A/B ?

Fritz Erni

FromFrom ‘ ‘blind compliance’ blind compliance’

to to ‘‘science and risk science and risk

based compliance’based compliance’

Ajaz Hussain, FDAAjaz Hussain, FDA

The Paradigm ChangeThe Paradigm Change

Key Key

in the Future ofin the Future of

ManufacturingManufacturing

Process UnderstandingProcess Understanding

Fritz Erni

What? Process Understanding

CAPABILITYLITY,PREDICTABIDESIGN,. INGUNDERSTANDPROCESS

Intended Use 1st PrinciplesModeling

OptimizationContinuous

ImprovementCAPA

Risk based Regulatory Assessment

DISCIPLINEEpidemiologyPharm. Engg.ClinicalClin.PharmPharm/ToxPharmaceuticsChemistryBiology

ORGANIZATIONMarketingInformation TechnologyQuality AssuranceManufacturingRegulatoryDevelopmentDiscovery

TIMETIACCGenericAER/Complaints.ApprovalPhase IIIPhase IIPhase IDiscovery

Ajaz S. Hussain

Fritz Erni

A Process is well understood when…

– all critical sources of variability are identified and explained;

– variability is managed by the process; and,

– product quality attributes can be accurately and reliably predicted over the design space …

• http://www.fda.gov/cder/guidance/6419fnl.htm

The PAT GuidanceThe PAT Guidance

Fritz Erni

Challenges to ‘Understanding’

Understanding involves Measurements

Fritz Erni

Challenges to Analytical Science

The need for increased Process understanding is a massive Boost for Analytical Science

Fritz Erni

Challenges to Analytical Science

adequate Tools?

Fritz Erni

Challenges to Analytical Science

adequate Tools !

Fritz Erni

Challenges to Analytical Science

We need the adequate Tools

Fritz Erni

PAT: Process Understanding

•Improved Process Knowledge to Identify and Remove Sources of Variability

•Identify Critical to Quality parameters

•Process understanding as input to Risk Management

•Control what is critical

Fritz Erni

What is Quality by Design

Elements of a QbD

• Systematic Development Approach• Formulation Understanding• Process Understanding• Packaging Understanding• Application of Quality Risk

Management• Advanced Control Strategy

Fritz Erni

Quality by Design

Conventional PD Quality by Design(ideal)Mainly empirical approach

A systematic approach

Quality assured by end-product testing and inspection

Quality assured by well understood product and process, moving controls upstream without relying on end-product testing as much as possible

Process is fixed, disallowing changes

Flexible process within design space, allowing continuous improvement

Focus on process reproducibility – often avoiding or ignoring variability

Focus on formulation and process robustness – understanding and controlling variability

Limited and simple IPC Extended PAT tools replacing the need for end product testing

Fritz Erni

What is ICH Q8

• Guideline for the description what is in P2

• Describes the minimal Standard for P2

• Opens door to get closer to the ‘Desired State’

• Science based• Includes Risk Management• Continuous improvement• Real Time Release

ICH Q8Door opener for Quality by Design

Fritz Erni

Design Space

The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and

approval.

Design Space• Is Key for claiming Process Understanding

• Process understanding is Key for Quality Risk Management

• QRM is the base for any Control Strategy

Fritz Erni

Design of Experiments (DoE)

Air flowIn

let t

empe

ratu

re

Degradation and fines

Air flowIn

let t

empe

ratu

re

Degradation and fines

Air flowIn

let t

empe

ratu

re

Degradation and fines

Air flow

Inle

t te

mpe

ratu

re

Fines

Air flow

Inle

t te

mpe

ratu

re

Degradation

Air flow

Inle

t te

mpe

ratu

re

Fines

Air flow

Inle

t te

mpe

ratu

re

Fines

Air flow

Inle

t te

mpe

ratu

re

Degradation

Air flow

Inle

t te

mpe

ratu

re

Degradation

Effect of inlet temperature and air flow on degradation and generation of fines

Fritz Erni

Examplain Design Space – Graphical Description

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

Fritz Erni

Quality Risk Management Q9

and the Control Strategy

Fritz Erni

The Quality Risk Management Process

Risk Review

Ris

k C

om

mu

nic

ati

on

Risk Assessment

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Ris

k M

an

ag

em

en

t too

ls

Fritz Erni

WaterContent

Drying

Granulation

RawMaterials

Compressing

PlantFactors

Operator

Temp/RH

Precompressing

Main Compressing

Feeder Speed

Press Speed

Punch PenetrationDepth

Temp

RH

Air Flow

Shock Cycle

DrugSubstance

P.S.Process Conditions

LOD

Diluents

P.S.LOD

Other

Lubricant

Disintegrant

Binder

Water

Binder

Temp

Spray Rate

Spray Pattern

P.S.

Scrape Down

Chopper Speed

Mixer Speed

Endpoint

PowerTime

Age

Tooling

Operator

Training

Analytical

Method

Sampling

FeedFrame

Cause and Effect Process

Fritz Erni

QRM Tools:Failure Mode Effects Analysis

(FMEA)Risk Assessment

Sub-StepEvent(Failure mode)

Effect

Sev

erit

y (S

)[1

<2<3

]

Pro

bab

ility

(P

)[1

<2<3

<4]

Det

ecta

bili

ty (

D)

[1<2

<3]

Ris

k fa

cto

r (S

*P*D

)

Granulation Drying water contentnot meet specification of degradation

2 3 1 6

Risk Reduction

Actions:Risk reduction strategy

Sev

erit

y (

S)

[1<

2<

3]

Pro

bab

ilit

y (P

)[1

<2<

3<

4]

Det

ecta

bil

ity

(D)

[1<

2<3

]

Ris

k f

acto

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)

Ris

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edu

cti

on

Comments

introduce online NIR 2 1 1 2 4 indirect measurment

introduce IPC analytic 2 2 1 4 2direct measurement; time consuming

humidity measurement in the exausting air

2 1 2 4 2indirect measurment; unspecifoc

Fritz Erni

Control Strategy• Justification of necessary controls

– Raw Materials Control– In-Process Controls– End Product Controls (if necessary)

• Based on Process and Formulation Understanding

• Drives the Process in the Design Space

• Based on Quality Risk Management• To ensure conforming Quality

according Specifications

Fritz Erni

Control Strategy

Unit OperationsAttributesControls

Content Uniformity NIR

Water Content – NIRParticle size – FBRM

Dispensation

Blending

Fluidized Bed Dryer

Packaging

Tableting

Identity-NIR

Blend Homogeneity -NIR

Granulation

Extent of Wet Massing - Power

Consumption

Air

Scale

Multivariate Model (predictsDisintegration)

Raw Materials

Fritz Erni

Q8 Design Space

Can the design space concept also be

applied to Analytical Methods?

Fritz Erni

Q8 Design Space

What is Analytical Method

Understanding?

Systematic Method DevelopmentHow to find max.no. of peaks at max.crit.resolution

pH of eluent A

tG

AN 1:1 MeOH

Cbuffer

40

70

30‘ 90‘

-0.6 +0.6

x 0.5 x 2.0

x 0.5 x 2.0Chetaeron

T[°C]

„Equal Band Spacing“

Increase speed by higher flowrate and reduced column length

different columns in different lengths(„POPLC“)

Dr.Imre Molnar,Institut für angewandte Chromatography,Berlin, Germany

Fritz Erni

Global Challenges

• Rising Global Regulatory Bar• Consent decrees and enormous fines from

manufacturing compliance deficiencies• Higher safety hurdles for marketing

approval• Industry’s pain for post approval changes• Biotech contribution less than expected• Government price control• Challenge of Earning Stakeholders Trust

Fritz Erni

Industry’s pain for post approval changes

• Many are method changes• Most of the changes are urgent• Many of them are

improvements

• US FDA has recognized the issue– Moheb Nasr (FDA) offers working together with

industry– Industry needs to show interest and takes it up

Fritz Erni

Design Space of a Separation Method

• What do we need to understand?• What does Industry need as flexibility

– Separation parameters fixed or with ranges – Separation parameters as a design space– Variability of HPLC columns included

• How is understanding related to the flexibility– How to put it in a dossier– How is it reviewed and approved

Fritz Erni

Design Space of a Separation Method

• The role of– Method development– Method validation– System suitability

• How to describe the enhanced understanding

• How to describe the design space• How to update the analytical design

space• What is the ‘regulatory flexibility’

Fritz Erni46

Summary The Vision of the desired state What is PAT and QbD ICH Q8 is a Door Opener for

Describing Quality by Design Including more Science and Risk Management

Introduces the Concept of Design Space Design Space Concept for Analytical

Methods

Fritz Erni

Alles zu messen was messbar ist -

Und messbar machen was noch nicht messbar ist!

Galileo Galilei1564-1642