ich guideline q14 analytical procedure developmentª apresentação_amanda_usp.pdf · drug testing...

ICH guideline Q14 Analytical Procedure Development

Amanda Guiraldelli, Ph.D.Scientist - Reference Standard Laboratory - U.S. Pharmacopeia

[email protected]

Agenda

Goals of analytical procedures

Analytical Procedures Development (APD):

Traditional x Enhanced approaches

Enhanced approach: Analytical Quality by

Design (AQbD)

Regulatory perspectives for APD and

AQbD: ICH Q14 - Analytical Procedures

Development

U.S. Pharmacopeia Contribution to APD

environment

2

© 2018 USP

3

© 2018 USP

Analytical Procedure Development

EARLY DEVELOPMENT

DRUG DISCOVERY

PRECLINICAL SAFETY STUDIES

EARLY FORMULATION DEVELOPMENT

TECNOLOGY TRANSFER

MANUFACTURING PROCESS

POST-MARKETING

SURVEILLANCE

DEVELOPMENTPOST

REGISTRATION

Phase IV post-approval studies todetermine specific safety issues

INV

ES

TIG

AT

ION

AL

NE

W D

RU

G A

PP

LIC

AT

ION

NE

W D

RU

G A

PP

LIC

AT

ION

PH

AS

E

I

PH

AS

E

II

PH

AS

E

III

CLINICAL TRIALS

The goal and purpose of the method should reflect the phase of drug development

Analytical Methods support preclinical

safety evaluations, pre-formulation studies,

and prototype product stability studies. Analytical methods are intended to

establish the identity, purity, physical

characteristics, potency of drug products

and evaluate drug performance

Methods are developed to support

drug testing against specifications

during manufacturing and quality

release operations, as well as during

long-term stability studies.

PROCESS UNDERSTANDING

Method development is a continuous process that progresses in parallel with the evolution of the

drug product, and may be refined/expanded, based on increased API and drug product knowledge.

4

© 2018 USP

Analytical method development


Method related activities are iterative,

particularly during early drug

development phases.

Changes encountered during drug

development may require

modifications to existing analytic

methods. R.W. Lee, L. Goldman, The Central Role Of Analytic Method Development And Validation In

Pharmaceutical Development, Life Science Connect. 2012.

https://www.particlesciences.com/docs/analytic_method_development_in_pharmaceutical.pdf

https://www.particlesciences.com/docs/analytic_method_development_in_pharmaceutical.pdf


Approaches used for analyticalprocedures development

“Enhanced approach”

Analytical Quality by Design (AQbD)

systematic approach which studies

multiple factors simultaneously to evaluate

the impact on method performance

“Traditional approach”

One-factor-at time experiments (OFAT)

testing of factors and their effects

one at a time instead of multiple factors

simultaneously.

6

© 2018 USP


Enhanced approach - Analytical Quality by Design (AQbD)

Input factors will be varied all at the same time using Design of Experiments (DOE).

Design of Experiments – DOE DOE is defined as a branch of applied statistics that deals with:

– planning, conducting, analyzing,

– and interpreting controlled tests to evaluate the impact of the factors on the process parameters.

DOE is a powerful data collection and analysis tool that can be used in a variety of experimental

situations.

Types of experimental design: Screening: Full factorial design, fractional factorial design, placket-burmann, mixtures design, optimal designs

Optimization: Central composite design, Box Benken, Doehlert etc.

Process/method understanding acquisition!

1. Montgomery. D.C. Designs and Analysis of Experiments. 8th edition. Wiley. 2013.

2. Lundstedt, T. et al. Experimental design and optimization. Chemometrics and

Intelligent Laboratory Systems 42 (1998) 3–40.

3. Hibbert. B. H. Experimental design in chromatography: Tutorial review. Journal of

Chromatofraphy B, 910 (2012) 2-13.

7

© 2018 USP


Enhanced approach - Analytical Quality by Design (AQbD)

REGRESSION

ANALYSIS:

methods used for the

estimation of

relationships

(Regression model)

between the analytical

response (y) and one or

more independent

variables

(x1,x2,x3...)

PROCESS

Variable 1 (x1) : Columns

Variable 2 (x2) : pH of mobile phase

Variable 3 (x3) : Organic solvent

INEPENDENT VARIABLES/INPUT FACTORS

Response 1 (y1) : Resolution between a critical pair

Response 2 (y2) :

Number of peaks with Rs 1.5

DEPENDENT VARIABLES/ANALYTICAL RESPONSES

𝒇 𝒙𝟏, 𝒙𝟐, 𝒙𝟑

𝒚 = 𝜷𝟎 + 𝜷𝟏𝒙𝟏 + 𝜷𝟐𝒙𝟐 + 𝜷𝟑𝒙𝟑 + 𝜷𝟏𝟏𝒙𝟏𝟐 +𝜷𝟐𝟐 𝒙𝟐

𝟐 +𝜷𝟑𝟑 𝒙𝟑𝟐 +𝜷𝟏𝟐 𝒙𝟏𝒙𝟐 +𝜷𝟏𝟑 𝒙𝟏𝒙𝟑 +𝜷𝟐𝟑 𝒙𝟐𝒙𝟑 +𝜷𝟏𝟐𝟑 𝒙𝟏𝒙𝟐𝒙𝟑 +ε

What can we do with the regression models?– Variables selection

• Identify analytical conditions which impact significantly on the analytical

responses

• The interaction between factors can be estimated

systematically.

– Analytical response prediction

• Access to experimental information in a larger region of the factor space.

• Identify analytical conditions for analytical response optimization

BEFORE TRYING TO

UNDERSTAND THE PROCESS

THE PREDICTION QUALITY OF

THE MODEL MUST BE EVALUATED!

STATISTICAL ANALYSIS! VALIDATION

8

© 2018 USP

AQbD - Regulatory Perspectives


ICH Guideline Q8: Pharmaceutical Development (2004)

Quality by Design concept (QbD)

“A systematic approach to development that begins with

predefined objectives and emphasizes product and process

understanding and process control, based on sound science

and quality risk management”

ICHQ8(R2) doesn’t explicitly discuss analytical method

development.

However, concepts apply to Analytical Procedure Development!

9

© 2018 USP

Analytical QbD Workflow


QUALITY TARGET PRODUCT PROFILE (QTTP)

ANALYTICAL TARGET PROFILE (ATP)

CRITICAL QUALITY ATTRIBUTES (CQA)

CRITICAL METHOD ATTRIBUTES (CMA)

CRITICAL PROCESS PARAMETERS (CPP)

CRITICAL METHOD PARAMETERS (CMP)

DESIGN OF EXPERIMENTS (DOE)KNOWLEDGE SPACE

DESIGN SPACE

WORKING POINTS

ROBUSTNESS TEST

CONTROL STRATEGY

1

2

3

4

5

6

ME

TH

OD

DE

SIG

N

LIF

EC

YC

LE

/ K

NO

WL

ED

GE

M

AN

AG

EM

EN

T

Allow continual feedback and feed-forward interaction among all steps

Meet and maintain method performance criteria

Quality by Design Approaches to

Analytical Methods - FDA Perspective -

American Association of Pharmaceutical

Scientists (AAPS) Annual Meeting,

Washington DC, 2011

Predefined objective that stipulates the performancerequirements for the analytical procedure

Analytical reponses which represent the quality of themethod and reflect method suitable performance

Analytical conditions (input factors) which impactsignificantly on method performance- Prior knowledge/initial risk assessment

ME

TH

OD

UN

DE

RS

TA

ND

ING

Select suitable experimental design and acquire data, Regression analysis/Statistical analysisDesign Space=Method Operable Design Region (MODR)Risk assessment

Select points for experimental verification and design space validation

Assign system suitabilitytests

10

© 2018 USP


AQbD workflow and available software

ACD/AutoChrom

Qb

DS

OF

TW

AR

E

FO

CU

SE

D O

N M

ET

HO

D D

EV

EL

OP

ME

NT

2. SELECTION OF EXPERIMENTAL DESIGN TYPE OF

3. EXPORT DATA MATRIX (EXPERIMENTS)TO CHROMATOGRAPHIC SYSTEMINSTRUMENT METHODS AND SAMPLE SET

4. EXPERIMENTAL ANALYSIS AND CHROMATOGRAM AQUISITION

5. DATA PROCESSING

6. IMPORT RESULTS (ANALYTICAL RESPONSES)

1. V

AR

IAB

LE

SE

LE

CT

ION

7. REGRESSION ANALYSIS

8. STATISTICAL ANALYSIS OF THE MODEL

9. RESPONSE PREDICTION, ANALYTICAL CONDITIONS SELECTION AND GREAT UNDERSTANDING ABOUT THE LIMITATIONS AND ROBUSTNESS OF THE METHOD **DryLab, Statistica, Matlab, Minitab, Design Expert, R program, Excel

S-Matrix

11

© 2018 USP

AQbD - Case study

Degradation prod:

Carbxylic acid

(0,9 % HCl 6M,

t.a., 10d)

Degradation prod.:

Imp. C Descarboxylated

(3,2% - HCl 6M 55°C 3

dias)Degradation prod.: N-oxide

(55,9 % - H202 0,3%, 4h)

-Degradation prod.:

N-desalkylated,

(1,1 % UV-A

0.6 % - H202 0,3%, 4h)

ANALYTICAL TARGET PROFILE (ATP)

Development of an indicating-stability method which is selective and robust for API, its impurities and

targeted degradation products (DP) quantitation (accurate and precise) in the API by UHPLC-UV

Note: selectivity studies will be evaluated using mass spectrometry.

STUDY IMPURITIES, API AND POTENTIAL DEGRADATION PRODUCTS PHYSICO-CHEMICAL PROPERTIES

12

© 2018 USP

AQbD - Case study

Pilot stress testing: Assign target degradation product

(e.g.: above notification limit recommended in the ICH guideline Q3A

Mixture of impurities, API and targeted degradation products

Screening 1DOE

Screening 2DOE

Optimization e robustness Study using DOE

●

●

●

Stress testing using final method

LC columns and pH screening

87 experiments (44h)

LC column and narrow pH range

Column temperature

Organic solvent

76 experiments (33h)

Robustnes study considering best performance:

– LC column and pH of mobile phase

– Column temperature and organic solvent

– 42 experiments (16h)

< 4 days!

DESIGN SPACEB

D

8.10

8.20

8.30

8.40

8.50

8.60

8.70

8.80

8.90

9.00

pH

(*)

25.0 26.7 28.3 30.0 31.7 33.3 35.0

KNOWLEDGE

SPACE

REFERENCE STANDARDS LABORATORY - BRAZIL

Auto-Scaled Chromatogram

Imp.

C (c

arbo

x. a

cid)

- 1.

864

PD

: N-o

xide

- 8.

393

PD

: Des

met

ylat

ed B

PD

- 9.

125

Imp.

A (a

cyla

ted)

- 10

.726

Bro

mop

rida

- 11.

261

Des

carb

oxyl

ated

Imp.

C -

13.4

19

AU

-0.010

0.000

0.010

0.020

0.030

0.040

0.050

0.060

0.070

0.080

0.090

0.100

Minutes

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00

Colorful shading area:Some accep. criteria is not met

(bad method performance)

White shading area:All acceptance criteria are met

(mean performance and robustness)

Method understanding facilitates:− Control strategies assignment

such as system suitability tests

− Method risk assessment

− Support for movements insidethe design space assuring robstunessand great method performance

− Lifecycle management

Final MethodPhenyl column (hybrid silica) (100mm x 2.0 mm x 1.9um)Column Temp. : 30°C (±3°C) Flow rate: 0.3mL/min±0.02Solution A: Amm. Bicarbonate 5mM pH 8.9 (±0.1)Solution B: ACN:THF (7:3) ±3%

13

© 2018 USP

Benefits of Application of QbD approach to Analytical Methods


Development of a robust method

High degree of analytical method understanding

Facilitate method risk assessment and strategies control assignment

Method lifecycle management

Regulatory flexibility: – Movements within “Design Space” are not

considered a change in method

– Need sufficient statistical power to support analytical

“Design Space”

Quality by Design Approaches to Analytical Methods - FDA Perspective - American Association of Pharmaceutical

Scientists (AAPS) Annual Meeting, Washington DC - October 25, 2011

14

© 2018 USP

Quality by Design (QbD)

R. Fisher

(England 1920-1930)

And G. Box

(1950 - 1960)

Design of experiments(DOE)

Dr. Joseph M. Juran

developed the concept

of Quality by design

(QbD) : “quality should

be designed into a

product, and that most

quality problems relate

to the way in which a

product was designed

in the first place”

FDA encourages risk-based

approaches and the adoption of

QbD principles in drug product

development, manufacturing, and

regulation.

“increased testing does not

necessarily improve product

quality. Quality must be built into

the product.”

ICH guidelines which outline QbD concepts

2004: Q8 Pharmaceutical development

2005: Q9 Quality risk managment

2007: Q10 Pharmaceutical quality system

2012: Q11 Development and Manufacture

of Drug Substance

EMA-FDA pilot

program for

parallel

assessment of

QbD applications

and AQbD Survey of

pharmaceutical

companies on

implementation of

AQbD concepts

ICH guideline Q14: Analytical

Procedure Development

new guideline is proposed to

harmonise the scientific approaches

of Analytical Procedure

Development

ICH guideline Q14:

2019: First draft

2020: Public consultation

1930-1960 1990 2002 2004 - 2012 2013 2017 2018 2019-2021

R. Fisher

(England 1920-1930)

And G. Box

(1950 - 1960)- develop analytical

methods based

on AQbD

- establish

methodology

for verification of the

design space

15

© 2018 USP

Analytical Quality by Design (AQbD)

Evaluating Progress in AQbD

Survey of pharmaceutical

companies on implementation of

AQbD concepts - 2017

Argentine, M. et al. Evaluating Progress in Analytical Quality by Design.

Pharmaceutical Technology. Vol. 41, issue 4, Pg.52-59.

69% of the companies had implemented AQbD

Some NDA applications applying AQbD have been approved

Business drivers and considerations:

– Better understanding of analytical procedures: improved

performance and robustness of the methods

– facilitate lab-to-lab transfer

– Time saving in developing robust methods

– Regulatory relief with operational flexibility

– Further discussion on experimental and statistical best

practice are warranted (guidances, case studies, etc)

– Variety in the level of detail of AQbD fillings

– Some of the regulators commented on the lack of

robustness testing

16

© 2018 USP


New ICH guideline

Q14 Analytical Procedure

Development

Lack of Analytical Development guideline which

should complement with guideline Q8(R2) and Q11.

Only results of Analytical Validation are often reported

and rarely performance evaluation with analytical

development outcomes are presented

Lack of guideline impedes opportunities for the

applicant to present a scientific basis for flexible

regulatory approaches (e.g., Quality by Design

concept) to post-approval Analytical Procedure

changes.

18

© 2018 USP


New ICH guideline


Development

Final Concept Paper -

Endorsed on 15 November

2018

The new guideline will provide an opportunity to

– present the outcome of Analytical Procedure

Development in traditional approaches

and in enhanced approaches

“Traditional approach”

set points and operating

ranges are defined and

control strategy is typically

based on demonstration of

method reproducibility and

testing to meet established

acceptance criteria.

“Enhanced approach”

risk management and

scientific knowledge are

used more extensively to

identify and understand

process parameters

ICH Q11: Development and

Manufacture of Drug Substance

19

© 2018 USP


New ICH guideline


Development

Final Concept Paper -

Endorsed on 15 November

2018

Some of main technical and scientific elements,

which require harmonization, include:

-The concept and strategy of enhanced

approaches for Analytical Procedures

-Performance criteria of Analytical

Procedures.

-In line with Q8 and Q11, greater

understanding of Analytical Procedure can

create the basis for more efficient, sound

science and risked-based change

management (e.g., using Analytical Quality

by Design principles).

- Key elements and terminology

20

© 2018 USP


New ICH guideline


Development

Work Plan and Business Plan

What is the time frame of the

project/milestones?

Nov. 2018: Final Concept Paper

June 2019: Finished the drafts to

be reviewed

Q4 2020: public consultation

Q2 2021: Step 4: adoption by

regulatory members

21

© 2018 USP

U.S.Pharmacopeia contribution to APD environment


<1225> Validation of Compendial Procedures

• 1990: precursor of ICH Q2. (1994/1996)

• Focus in chromatographic procedures

<1226> Verification of Compendial Procedures

<1224> Transfer of Analytical Procedures

• Created in response to users needs

<1210> Statistical tools for procedure validation

• USP 41

PF 39(5) Lifecycle Management of Analytical Procedures

Method Development, Procedure Performance Qualification,

and Procedure Performance Verification

A new Expert Panel started on Feb 2019

PF 42(5) Analytical target profile (ATP) Structure

and application throughout the analytical lifecycle

PF 42(5) Analytical control strategy

Quality risk management in the lifecycle of the

analytical procedure

PF 43(1) The Analytical Procedure Lifecycle <1220>

Design, development, qualification, and continued

verification of the analytical procedure

USP Stimuli articlesUSP General Chapters

http://files.pharmtech.com/alfresco_images/pharma/2017/10/12/57f7cb3d-729a-4804-86fd-69f70c97058e/LCGC5_i3.jpg?__hstc=174258557.e281b954d5f88e53a314dbfc92319fad.1540399475575.1540399475575.1540399475576.1&__hssc=174258557.1.1540399475577&__hsfp=2403711691


New ICH guideline

Q14 Analytical

Procedure

Development

Enhanced approaches for

APD

Increase of method

robustness and understanding

Science and Risk based

methodology

Knowledge and analytical design space

Risk assessment

and management

Control strategy

Method lifecycle

management (continual

improvement)

Quality built

into the

analytical

method design

Amanda Guiraldelli, Ph.D.

Scientist - Reference Standard Laboratory - U.S. Pharmacopeia

[email protected]

ich guideline q14 analytical procedure developmentª apresentação_amanda_usp.pdf · drug testing...

Documents