EDQM: 50 YEARS OF LEADERSHIP IN THE QUALITY OF … · • Brief overview of ICH Q8, Q9, Q10, Q11 • Details of Ph.Eur. 2.9.47 Uniformity of dosage units using large sample sizes

EDQM: 50 YEARS OF LEADERSHIP IN THE QUALITY OF MEDICINES

PAVING THE WAY FOR THE FUTURE

6-8 October 2014Strasbourg, France

WORKSHOP

QUALITY BY DESIGN

1

The Pharmacopoeia and QbD

7 October 2014

Dr. Øyvind Holte

Norwegian Medicines Agency/ EDQM PAT WP

Overview

• Quality by Design (QbD)

– High-level principles

– Role of the pharmacopoeia

• EDQM PAT working party

– Background, efforts and future prospects

• European pharmacopoeia and QbD

– General guidance in the pharmacopoeia

– Recent revisions, interpretation and practice• Ph.Eur. 2.9.47

Uniformity of dosage units using large sample sizes

• NIR, Raman, General notices2

2

Quality by DesignPrinciples

• Demonstration of product quality:

– QbD: Focus shifted from end testing of the productvia product knowledge to process control

3

End testing

Processcontrol

Enhancedproduct

knowledge

Quality assurance/ Control strategy

Quality by DesignRole of the Pharmacopoeia

• European Pharmacopoeia– Quality standards

• General dosage forms, drug substances, excipients, (drug products)

– Harmonised general methods

• QbD often involves on-line analysis during manufacture, rather than off-line end testing– Is this compatible with pharmacopoeial requirements?

• QbD is all about achieving and demonstrating therequired product quality– This is well within the scope of the Pharmacopoeia!

4

Contributing to the quality of

medicines

3

EDQM PAT working party

• Work programme

– Revision of relevant chapters

– Consider need for new chapters

• Key chapters

– Uniformity of dosage units (Ph.Eur. 2.9.40)

– Near infrared spectroscopy (Ph.Eur. 2.2.40)

– Raman spectroscopy (Ph.Eur. 2.2.48)

– Ph.Eur. 1. General notices

• Current and future status– PAT is not a stand-alone area, but should be considered within

the remit of any type of analytic methodology5

European Pharmacopoeia and QbD1. General notices

• An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph

• The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process.

• Real-time release testing […] is not precluded by the need to comply with the Pharmacopoeia

6

4

European Pharmacopoeia and QbD5.15 Functionality-related characteristics

• FRC sections are non-mandatory

• FRCs are not exhaustive, but they are typical for the excipient:

– Particle size distribution

– Powder flow

– Bulk and tapped density

– Viscosity

– Melting point

• Knowledge of FRCs may facilitate the applicationof process analytical technology (PAT)

7

European Pharmacopoeia and QbDQbD-relevant chapter: Uniformity of dosage units

• Specific issues raised on the UDU test (2.9.40):

– Acceptance criteria directly linked to the prescribed sample size N = 30

– Rigid requirement: no single unit outside +/- 25 %.N >> 30: one or few largely deviating units is expected?

– Improved batch knowledge with large sample was not appreciated in the acceptance criteria

“The pharmacopoeia should not represent a barrier/ disincentive to the implementation of PAT/ QbD”

ksXMAV

8

5

European Pharmacopoeia and QbDQbD-relevant chapter: Uniformity of dosage unitsPh.Eur. 2.9.47

• Option 1– Parametric

Depending onsample size:

Limit for number ofunits outside(1 ± L2 x 0.01)T

• Option 2– Non-parametric

Depending onsample size:

Limit for number ofunits outside(1 ± L1 x 0.01)T

(1 ± L2 x 0.01)T

ksXMAV

9~90 % probability to pass Ph.Eur. 2.9.40 on any small sample

European Pharmacopoeia and QbDQbD-relevant chapters: NIR, Raman

• 2.2.40 Near-infrared spectroscopy

– revised in parallel with the EMA NfG on NIRs

• 2.2.48 Raman spectroscopy

• Revised to adequately describe equipmentand procedures suitable for in-line analysis

10

6

European Pharmacopoeia and QbDQbD-relevant chapter: 1. General notices

Demonstration of compliance with the Pharmacopoeia

• (2) An enhanced approach to quality control could utiliseprocess analytical technology (PAT) […] strategies as alternatives to end-product testing alone.

Real-time release testing Parametric release in circumstances deemed appropriate by the competent authority is thus not precluded by the need to comply with the Pharmacopoeia.

Ph.Eur. 8.2

11

European Pharmacopoeia and QbDSummary

Ph.Eur. provides quality standards

The manufacturer must assure his productcomplies with these standards

Ph.Eur. requirements apply regardless ofcontrol strategy

QbD/ PAT is one way of demonstrating quality

This approach is fully in line with Ph.Eur.

1. General notices

5.15 Functionality-related characteristics

12

7

Back-up slides/ References

• High-level overview of QbD and PAT analytical methods as concepts

• Brief overview of ICH Q8, Q9, Q10, Q11

• Details of Ph.Eur. 2.9.47 Uniformity ofdosage units using large sample sizes

13

Quality by DesignOverview

• Quality can be planned

• QbD for pharmaceutics

– US FDA initiative (2004)

– ICH Q8, Q9, Q10, Q11

– European Pharmacopoeia

14

8

Quality by DesignOverview: PAT analytical methods

Traditional analytics

• Off-line testing

– Starting materials

– Isolated intermediates

– End products

• Small sample size

• Destructive

• Delayed results

‘PAT analytics’

• On-line/ in-line testing

– Starting materials

– Intermediates

– End products

• Sample size ~100 ++

• Non-destructive

• Immediate results

Enables dynamic feed-back and feed-forward controls15

Quality by DesignRegulatory guidance: ICH

Q8: Pharmaceutical development

– quality target product profile (QTPP)

– Design of experiments

– design space

– control strategy

16

9


Q9: Quality risk management

17


Q10: Pharmaceutical quality system

– ISO 9000

– GMP

– ICH Q7

18

10


Q11: Dev. and manufacture of drug substances

– Chemical and biotechnological/ biological entities

– Q8, Q9 and Q10 applicable to drug substance

– Drug substance quality – link to drug product

– Starting material definition

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Ph.Eur. 2.9.47Uniformity of dosage units using large sample sizes

• Details of the development and interpretation of themethod can be found in– Ø. Holte and M. Horvat 2011. Evaluation of uniformity of dosage

units using large sample sizes. Pharmeuropa 23(2): 286-293

– Ø. Holte and M. Horvat 2012. Uniformity of Dosage Units Using Large Sample Sizes. Pharm Sci Technol 36(10): 118-122

– Ø. Holte and M. Horvat 2014. Letter to the Editor: Statistical Properties of Large Sample Tests for Dose Content Uniformity. Therapeutic Innovation & Regulatory Science. DOI 10.1177/2168479014531761

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11

Ph.Eur. 2.9.47Uniformity of dosage units using large sample sizes

• Probability to pass the test (operation characteristics curves)

– the sample provides an estimate of the batch

21

Ph.Eur. 2.9.47 Comparison of 2.9.40 and 2.9.47

• Simulated batch distributions

22

12

Ph.Eur. 2.9.47 Probability to pass the test (n=500)

23

Ph.Eur. 2.9.47 Comparison of 2.9.40 (n=30) and 2.9.47

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13

Analytical QbD andPharmacopoeialMonographs– a vision

Dr. Oliver Grosche

Efpia TDOC Subteam on Analytical Design Space

Pittcon 1970 – first mentioning “HPLC”

1970’s:

• Particle size d= 10 µm

• pressure p<80 bar

1980’s:

• d= 5 µm

• p<250 bar

1990-Millenium:

• d= 3-4 µm

• p<400 bar

Now:

• d= <2 µm

• p<1000 bar

Modernization of analytical technology –Analytical Rocket Science versus HPLC

5 0 Y E A R S E D Q M W O R K S H O P 2

1964: Start ofELDO / ESRO

1970’s: ESA formed/ COS-B• measurement of gamma ray

emission of the universe

1980’s : Giotto Mission,

• spectral evidence of organic material on comet Halley

Millenium: ISO mission• most sensitive IR telescope at the time

Now: Rosetta Mission

• , e.g. TOF-MS for comet dust analysis

Majority of Ph. Eur.Monographs

14

3

No change – No risk?

Risks associated with or without analytical changes

no change change

Loss of data consistency

Marginal Innovation

Change to non-standard technology

Loss of long-term experience with method

Supply issues with “old” materials and parts

Outdated technology

Non- Compliance with newest regulations

Not adequate to reflect manufacturing process

changes

Change decisions must be made with respect to Patient safety Drug availability Time for

implementation Costs

Balanced Innovation

5 0 Y E A R S E D Q M W O R K S H O P

General chapter 1.1 – accelerating innovation?

Alternative methods. ◀The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.


How can this be demonstrated / ensured for an alternative analytical method?

Method performance standards as enabler

15

5

What does analytical QbD stand for?

Good Method Design

Good Method Understanding

Good Method Risk Control

Analytical Target Profile (ATP)

Method performance criteria

Risk Mapping

Design of Experiments and Multivariate

statistical Analysis

?

Method Control Strategy:• Risk based SST• Parameter

Ranges

Good Operational Flexibility

Good Change Control

Method Development

Report

ChChange assessed

versus pre-defined method

performance (ATP)


6

Analytical Target Profile (ATP)

Predefined method performance

Result Variation Criteria Accuracy and Precision(or better: Total Error)

Performance Criteria

Specificity Intended Purpose Method Range Operation Environment (Business Aspects)

Validation Criteria

e.g. Linearity Limit of Quantitation Stability of Solution

SST Criteriae.g. Peak Resolution Repeatability of injection

ATP

Result

Context

Technology

Parameter


16

ATP Example


Requirement Method performance criteriaAccuracy Impurity A: ≤ 80-120 % of true value

Impurity B: ≤ 75-125% of true value

Precision ofreportable result

Impurity A srel ≤ 10%

Impurity B srel ≤ 15%

Intended Purpose

Quantification of manufacturing process related impurity (not a degradation product)

Range Impurity A: at least 0.05%-0.6%

Impurity B: at least 0.05%-0.12%

Specificity No interference of the quantification of the specified impurities by

• other related substances C, D, and E

• the salt forming agent

with Impurity A,B or the API. Operating conditions and Environment

The analytical procedure must be applicable for use in a standard analytical QC laboratory environment of ADS Pharma for routine analysis. The test procedure must be stable for at least 24 h of consecutive analyses.

Advantages of the ATP concept for the Ph. Eur.

Facilitation of Assessment of Methods from multiple manufacturers

Enabling balance between cost/safety of public standards (costly high end technology standard techology)

Predefinition of Method Interchangeability with public standards (Pharmacopoeial Compliance)

Facilitation of change control for individual monographs

ATPs can be retrospectively defined for already existing monographs to anticipate future changes

May be used as trigger to evaluate monograph revisions


17

9

Analytical Change Control through drug lifecycle

Preclinical Development

Clinical Development

Marketed (Exclusive)

Marketed (Generic)

GLP

• Internal change control

• Impurity profile of Tox studies traceable

Investigational GMP

• Internal change control

• Safety of patients in clinical trials

• Consistent analytical profile of development drugs during process upscale

GMP

• External change control: Health Authorities

• Safety of patients

• Consistent profile of manufacturing Process

GMP

• External Change control via HA’s and Pharmacopoeias

• Safety of Patients

• Consistent drug profile amongst multiple manufacturers


How to ensure a consistent drug profile?

10

Method AMethod BMethod C

Similar efficacy and safety

different API, same mechanism of action

e.g. “Me-Too’s” Bioequivalence

Same API, different formulation“Generics”

“Technical Equivalence”

Same Specification limits

Equivalent analytical methods

Conclusions for similar efficacy and safety based on technical reasons only possible if full linkage on all levels is given

Level A

Level B

Level C


18

Risk Control Strategy


Risk by wrong pass/fail decision for measured quality attribute

Risk by deviation from operation parameters

Risk by use of a certain technology

Industry

Pharmacopoeias

Health Authorities

Health AuthoritiesResult

Context

Technology

Parameter

Establishing analytical QbD elements into a Pharmacopoeial Monograph

Monograph Classical Enhanced

Method performance

Limited information, can only be partially derived indirectly from SST, specifications and transparency list

Clear definition of a method performance standard through ATP, binding

Method description

High level, binding fordescribed parameters

Detailed example method, facilitated alternative method through ATP

MethodParameters

Set-points Validated ranges within MODR (uni- or multivariate)

System Suitability Standardized with some mandatory tests through general chapters

Risk based SST as part of the method control strategy

Reference Standard

Connected to method Connected to ATP


19

Conclusions

An analytical innovation lag of 10-30 years may exist for pharmacopoeial methods

Ph. Eur. general chapter 1.1 supportive for alternative innovative methods

No guidance is given in Phar. Eur. on how to demonstrate interchangeability

The ATP concept may help to balance establish method interchangeability

Enhanced Pharmacopoeial Monographs may help to adapt the analytical method standards to the operational environment of multiple manufacturers


Thank You

EDQM Efpia “Analytical Design Space” Subteam:Melissa Hanna Brown (Pfizer)Jörg Hoffmann (Merck KGaA)Joachim Ermer (Sanofi)Christof Finkler (Hoffmann-La Roche), Stefanie Katzenbach (AbbVie)Phil Nethercote (GSK)Andy Rignall (AstraZeneca)Thomas Uhlich (Bayer)Kieran McLaughlin (Merck)Thorsten Sokoliess (Boehringer Ingelheim)


20

Backup Slides


Failure Mode Effect Analysis of Methods


Overall risk

Frequency Impact Detectability0

10

0

10

0

10

Patient riskProcess risk

Occurrence per sample and/or test

Clarity/Detail of instructionIndication of system suitability

low

high high

highlow

lowhigh

low

Identification of Critical Parameters

FMEA methodology to help to define allowable variations in Standard Tests

Risk based SST criteria for Monographs

21

Multivariate Experimental Design


low set high

Gradient slope

Temperature

pH

Buffer conc.

Wavelength

Univariate 1 Univariate 2

Multivariate 1 Multivariate 2

Selection of a Method which runs robust in multiple companies and countries

Establishment of Parameters/Ranges that can be adjusted for specific methods to meet SST criteria

Risk based Impurity Profile / Selectivity


Component Definition RequirementSpecified components

Regularly monitored (and qualified) related substances (by- and degradation products), Specified process related impurities

Specificity for all individual specified components obvious/demonstrated.

Unspecified regularcomponents

Unspecified related substances (by- and degradation products) and unspecified process related impurities regularly present in some or all batches of current manufacturing route/process or known degradation pathway. Components used as critical attributes/indicators for process control.

Specificity for unspecified regularly controlled components obvious/demonstrated

Unspecified potential components

Related substances for which the test method has the potential to separate but did not occur in batches of current manufacturing route/process or known degradation pathway.

Demonstration of Specificity beneficial but not required if related substances did not occur

Clear categorization will support monograph specifications and transparency list

Support specificty requirements for ATP and future monograph changes

22

Description of Method Design Space


Increased clarity which method parameters may be varied to meet SST criteria

Moving from method set-points to method parameter ranges

Level Concept for Analytical Changes


RR

C

T

P

20

Within design space

Same Technology

Same performance

characteristics

Analytical method validation tests &

criteria

Method independent performance tests

and criteria

System Suitability test &

criteria

Level 0 Level 1 Level 2

Very similar or same method

Same Technology

Same performance

characteristics

Very similar or same method

Same Technology

Same performance

characteristics

Level of comparison

not possible

(Level 3: all others)

Change control and experiments are proportionate to the risk of change

Safe changes in-between techologies become manageble through ATP

Safe Monograph Modernizaton

ATP

23

21

How is everything connected – the classical understanding

Specifi-cations

Link to specifications, e.g. range

Analytical Method + SST

Link to Reported test/value

Validation and Acceptance criteria

Link to Technology/experiments selected

Alternative method

Comparability demonstrated by compliance to acceptance criteria, e.g. via cross validation

Reference Standard


22

Potential QbD Scenario

Technology

QTPP

Analytical TargetProfile

Validation

1

Performancecriteria

Reference method

MODRMODR

Results

Control strategyon technology MODR

Method 2 Validation

2

Comparability demonstrated by compliance to performance criteria

Exte

rna

l ch

an

ge

co

ntr

ol

Inte

rna

l ch

an

ge

co

ntr

ol

Post Approval Change Management protocol

Post Approval Change Management Protocol:

allows a pre-assessment on potential changes

Reference Standard


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EFPIA Brussels Office

Leopold Plaza BuildingRue du Trône 108B-1050 Brussels - Belgium Tel: +32 (0)2 626 25 55

www.efpia.eu

25

Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)

Application of QbD to analytical methods - a regulatory perspective

Dr. Jobst Limberg- Bundesinstitut für Arzneimittel und

Medizinprodukte (BfArM)


• Views and opinions expressed in this presentation are those of the presenter

Disclaimer

2

26


• Suitable for intended purpose

• Validation characteristics (ICH Q2) Specificity Accuracy (of the mean) Linearity & range Limit of Detection, Limit of Quantitation Precision & intermediate precision (ruggedness) Robustness

• Includes sample preparation, reference substances, etc…

Analytical validation - overview

3


• No validation data required Pharmacopoeial test procedures

• Full validation necessary in the dossier for test procedures: used for batch release (end-product testing or real time release

testing) used for exploratory stability studies

• In case of variations When is a new validation necessary? What has to be done? What are the acceptance criteria?

Regulatory perspective on validation of analytical test procedures

4

27


• Variation of a test procedure New methods should be equal or better concerning the validation

parameters

• Variation during ongoing stability studies equivalence of results in terms of accuracy of the mean and

intermediate precision

• Adding a second, alternatively used test procedure Different equipment at different production sites Real time release test procedure differs from reference test

procedure for batch release Both methods should be equal/equivalent/similar/not

significantly different

Comparison of two analytical test procedures intended for the same purpose / statements

5


Comparison of two analytical test procedures –four scenarios on a dartboard

6

similar resultssimilar precisionsame systematic error

similar resultsdifferent precisionsimilar systematic error

Different resultsdifferent precisionsystematic error – yes and no

Similar resultsSimilar precisionno systematic error

28


X/y graph plus linear regression for two test procedures with different systematic error

7


Equivalence decision positive (inside the acceptance limits), but significant differences

8

29


• The discriminatory power to distinguish between “good” and “bad” batches should be comparable. O.k. for regulators, best scenario

• Over-discriminatory power leads to rejection of good batches (type II error) Also o.k. with regulators, but may be costly for industry

• Under-discriminatory power leads to releasing of bad batches (type I error) Not o.k. for regulators

Comparison of analytical test procedures -parallel testing / regulatory view

9


• Systematic approach to method development

• Analytical target profile ≡ acceptance criteria of validation plan

• Method operable design region (MODR), i.e. limits for procedural parameters in which the test procedure is suitable for its intended use

EFPIA approach (white paper)

10

30


• Analytical target profile should be restricted to test procedures based on the same physical methodology

• Method operable design region should be based on design of experiments

• Regulatory environment: Variation regulation has to be followed Post approval change management protocol allows up-front

information about potential future changes Assessment of analytical development and validation is part of

licensing and not of GMP inspections

Response to white paper by regulatory agencyEMA (joint QWP and BWP) (I)

11


• Approach restricted to specific quality attributes (?) Critical quality attributes Some test procedures are able to find the “unexpected”, which

may not be valid for another The discriminatory power to find new (unknown) impurities is not

predictable Knowledge gaps due to the complex nature of a test, e.g.

biological activity measurements In case of applying another physicochemical methodology, the

acceptance criteria for validation parameters may change

Response to white paper by regulatory agencyEMA (joint QWP and BWP) (II)

12

31


• Comparability of results obtained by alternative tests

• Two alternative test procedures for batch release at one manufacturing sites will constitute GMP problems

• No testing into specification acceptable

• Change inside a stability study may be problematic due to its explorative nature

Response to white paper by regulatory agencyEMA (joint QWP and BWP) (III)

13


• Operable design space: Small ranges for analytical parameters are already acceptable

according to ICH Q2 – robustness Ranges for analytical parameters are already acceptable according

to the European Pharmacopoeia

• Acceptability is based on data of a single methodology, which has been evaluated

• How to transfer this flexibility of analytical parameters from HPLC to NIRS and vice versa

Response to white paper by regulatory agencyEMA (joint QWP and BWP) (IV)

14

32


• Current guideline ICH Q2 allows small variability in analytical parameters – robustness

• Variation regulations allow flexibility for improvement

• Post approval change management protocol as a tool to implement planned changes in a shorter timeframe

• Once ICH Q2 will be under revision, some ideas may be incorporated

• Examples and requirements of ICH Q2 are focussed on chromatographic test procedures and should be extended to cover also spectroscopic in-line and on-line methodologies

Conclusions

15

Thank you for your attention!


33

Documents

EDQM: 50 YEARS OF LEADERSHIP IN THE QUALITY OF … · • Brief overview of ICH Q8, Q9, Q10, Q11 • Details of Ph.Eur. 2.9.47 Uniformity of dosage units using large sample sizes