ich q2/q14: reflections for vaccines€¦ · ich q2/q14: reflections for vaccines casss eu cmc...

ICH Q2/Q14: Reflections for VaccinesCASSS EU CMC Strategy ForumMay 2019

Cristiana CampaGSK Vaccines

Outline

2

➢ QbD-driven analytical strategy for vaccines

➢ Analytical Target Profile (ATP): case study

➢ ATP implementation supporting innovation

➢ Challenges and opportunities

➢ ICH Q14 and ICH Q2 (R2) supporting modernand robust analytical strategies

vaccines

Vaccines developmentPoints to consider

Complex products and processes → difficult characterization

Wide variety of possible vaccine categories/ structural features, →limited possibility to leverage information from different product types

Analytical strategy: structural and formulation changes →impact on immunogenicity

Knowledge of antigen structure, formulation, analytics and process are instrumental for attribute selection and ranges to be clinically explored

Aggressive timelines : product, process, analytical development (especially in case of disease outbreaks)

3

Analytics: clear definition of test purpose → product

& process expectation

• Well-defined methods desired from early development→ visible changes detected during product & process development/ life cycle

Product & Process«clients» expectation

• Minimal change of methods occur during all life cycle, with some resistance to changes or improvements

Consequences

• Product and process requirements built over time (platform concept is not fully in place for vaccines)

• Innovative analytical technologies required due to complexity

Challenges for vaccines

• Analytical Target Profile (ATP) defined with clients from early development→ Ideal performance of the analytical methods with no link to technologies

Solution

4

Analytical strategy driven by QbD is a key element of

the control strategy

Analytical Strategy for product and process

Analytical requirements (Analytical Target Profile,

ATP)

Technology and methodselection based on ATP

Method parameters impacting performance

and their ranges

Method qualification and validation as applicable,

using ATP to defineacceptance criteria

5

Outline

6

➢ QbD-driven analytical strategy





vaccines

Why is Analytical Target Profile so relevant?

7

Patrick Jackson , Phil Borman, Cristiana Campa, Marion Chatfield, Mark Godfrey, Peter Hamilton, Walter Hoyer, Francesco Norelli, Rachel Orr, and Tim Schofield“Using the Analytical Target Profile to Drive the Analytical Method Lifecycle”, Analytical Chemistry, 91 (2019) 2577–2585.

Defines the objective of the test and its performance expectations based on product/ process needs

Is linked to the attribute to be tested, and not to a specific analytical method/ technology

Has pre-defined requirements, updated and refined based on product/ process needs throughout lifecycle

Drives analytical method selection and development

The

ATP

8

ATP exampleAmount of Free Saccharide (FS) in a glycoconjugate

Coupling Chemistry(covalent linkage)

+Carrier Protein

Polysaccharide Polysaccharide-

Protein Conjugate

Attachment

point

Polydispersionscontaining a

variable number of identical

repeating units

Minutes

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

AU

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

AU

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035PDA - 200nm

BulkRS2901(GGC_060)_TQ_100mMH3BO3_25mMSDS

BulkRS2901(GGC_060)TQ_100mMH3BO3_25mMSDS 10-22-2007 8-11-33 PM -Rep5.dat

unconjugated-“Free” PS

unconjugated“Free” protein

Glycoconjugateeg Group B Streptococcus

PURPOSE: Measure the content of Free (unconjugated)

(Poly)saccharide, to estimate its relative amount vs. Total

Saccharide as a process or product related impurity

9

ATP exampleAmount of Free Saccharide (FS) in a glycoconjugate

Attribute range Specificity Combined uncertainty Accuracy (Bias) Precision

Criteria RationaleCriteria and

RationaleCriteria Rationale Criteria Rationale Criteria Rationale

from 4 to

1000 μg/mL

Since Total

Polysaccharide

concentration is

in the range 400-

2000 μg/ ml and

% of FS to be

quantified are in

the range 1% to

50%, (%FS lower

than

1% considered as

not relevant to

the product

perspective).

No interference

with

conjugated

polysaccharide,

carrier protein,

and buffer

components

≤ 30% across

attribute

range

(with 95%

probability)

Based on: a) Target development range

(also expected to contain process

variability) is ≤10% in terms of %FS and

b) specification upper limit (not yet

clinically established) is foreseen to be

NLT 20%” as %FS:

30% combined uncertainty considered

acceptable since:

1. Even at the upper edge of target

development range, the proposed

combined uncertainty corresponds to a

large safety margin with respect to risk

of having a batch out of the foreseen

spec limit.

2. For a process/product related impurity

(FS), to be compared with the target

active ingredient (TS), expected < 10% of

TS, the “relative” combined uncertainty

of FS vs. TS will be lower than about 3 %,

that is fully acceptable for a

process/product related impurity.

≤ 11% across

attribute

range

Accuracy

requirement

calculated

according to

the combined

uncertainty

and precision

requirements

≤10% across

attribute range

With 95%

probability an

individual

value will thus

lie within 83-

121% of its

(possibly

biased) long-

term average

(appropriate

for monitoring

stability)

Patrick Jackson , Phil Borman, Cristiana Campa, Marion Chatfield, Mark Godfrey, Peter Hamilton, Walter Hoyer, Francesco Norelli, Rachel Orr, and Tim Schofield“Using the Analytical Target Profile to Drive the Analytical Method Lifecycle”, Analytical Chemistry, 91 (2019) 2577–2585.

10

ATP example- (attribute) range and specificity

• This is the expectedrange of the attribute in the sample

• The analytical procedure range is not part of the ATP and will be definedafter method selection, development and validation

Attribute range

Criteria Rationale

from 4 to 1000 μg/mL

Total Polysaccharide

concentration is in the range

400-2000 μg/ ml and % of FS to

be quantified is in the range 1%

to 50% (%FS lower than

1% considered as not relevant

to the product perspective).

Specificity

Criteria and Rationale

No interference with conjugated polysaccharide, carrier

protein, and buffer components

11

ATP example- combined uncertainty

• Combined uncertainty criteria combine accuracy and precision into a requirement which is acceptable for a measurement.

• Input for combined uncertainty is the target development range and (when available/ applicable) the specification of the product. It is not related to any specific analytical technology

Combined uncertaintyCriteria Rationale

≤ 30%

across

attribute

range

(with 95%

probability)

Based on: a) Target development range (also expected to

contain process variability) is ≤10% in terms of %FS and b)

specification upper limit (not yet clinically confirmed) is

foreseen to be NLT 20%” as %FS:

30% combined uncertainty considered acceptable since:

1. Even at the upper edge of target development range,

the proposed combined uncertainty corresponds to a large

safety margin with respect to risk of having a batch out of

the foreseen spec limit.

2. For a process/product related impurity (FS), to be

compared with the target active ingredient (TS), expected

< 10% of TS, the “relative” combined uncertainty of FS vs.

TS will be lower than about 3 %, that is fully acceptable for

a process/product related impurity.

12

ATP example- combined uncertainty inputsTarget development range and specifications

13

ATP example- bias and precision…still relevant when using combined uncertainty

When using combined uncertainty criteria individual precision and accuracy evaluation may also be necessary because, depending on the measurement purpose, there may be the need to be more restrictive on accuracy or precision.

Accuracy (Bias)

Criteria Rationale

≤ 11% across

attribute range

Accuracy

requirement calculated

according to the combined

uncertainty and precision

requirements

Precision

Criteria Rationale

≤10% across

attribute range

With 95% probability an

individual value will thus lie

within 83-121% of its (possibly

biased) long-term average

(appropriate for monitoring

stability)

14

ATP example- bias and precision…and link with combined uncertainty

For a given combined uncertainty, 2 out of 3 parameters (bias, precision andprobability to meet the requirement) can be specified and the missing 3rdparameter is computed.

Acceptable combined uncertainty = 30% (multiplicative)p

rec

isio

n m

ea

sure

GC

V(%

)

p (%)

–

80accuracy measure (%)

90 100 110 120 130

The defined geometric coefficient of variation and derived multiplicative systematic error whichassure the required maximum combined uncertainty with ≥95% probability

15

ATP example- how was ATP used?… for NEW method selection and performance evaluation

• Different technologies were screenedfor suitability

• A new Micellar Capillary Electrophoresis with UV detection method was selected as the best choice (ATP requirements fulfilled), despite prior knowledge would have suggested the use of a chromatographic method

• Method development and validationwere executed following ICH Q2(R1)approach for quantitative methodsapplied to separation techniques, andATP requirements were used asvalidation criteria for accuracy (bias)and precision.

Analytical Strategy for product and process

Analytical requirements (Analytical Target Profile,

ATP)

Technology and methodselection based on ATP

Method parameters impacting performance

and their ranges

Method qualification and validation as applicable,

using ATP to defineacceptance criteria

After analytical technology selection, risk of failure can be limited through:

▪ Method development including QbD elements (eg applying a risk-based approach and, possibly, multi-variate studies), with finalverification of performances, to be compliant with ATP

▪ Establishment of a robust reference standard strategy (thoroughcharacterization, stability studies/ definition of storage conditions, use for method performance monitoring)

Note: these activities are critical also to ensure adequate bridging betweenmethods, if needed during life cycle management (eg for introduction of new technologies, or if ATP is refined after QTPP revision duringdevelopment)

Method development and reliability assessment

16

Outline

17






vaccines

Use and best timing for ATP establishment depend on the

attribute/ product

In both cases, ATP supports analytical methods optimization/technologies replacement as performance comparison qualifier (existingvs new method)

Vaccines (product-specific attributes)

Platform products/ attributes - eg small molecules

18

No prior knowledge

ATP defined as early as possible

Drives method selection,

development and validation

Well-established attributes

ATP needed at validation time

Captures validation

acceptance criteria

Why is continued innovation in the analytical space a

must?

➢During development

Advances in analytics for vaccine products can be leveraged toimprove knowledge of CQAs, thus allowing better control strategydevelopment prior to process validation, especially in acceleratedscenarios.

➢After launch

It is important to support introduction of new technologies as theyare demonstrated to improve control strategy and ensuring up-todate monitoring of safety and efficacy

19

20

CQA spec ranges based on demonstrated product safety or efficacy & stability

QbD- driven specs development as input for ATP→ no

need to modify specs range, in case of method change

• Technology- independent ATP expectations are set based on product requirements

• In case of a change, new and old method need to complywith the same ATP

Since expected attribute range is an input for the ATP, a methodchange does not imply modification of specification ranges

21

Historical data-driven specifications→ (retrospective)

ATP helps assessing current testing strategy

CQA spec ranges based on available manufactured lots release/ prior knowledge & stability

• Retrospective ATP establishment is helpful to challengeexisting methods and/ or support bridging to new ones.

• This is especially relevant for vaccines, due to their long lifecycle

A change in specification may occur in case of method change(after the first ATP retrospective implementation)

Main

Drawbacks

Traditional

analytical

methods for

product

release

CQA

Pyrogen testing in vaccines development: from the past..

22

Case study

Bexsero

Pyrogenic and

Endotoxin content

RPT

Limit test (PASS/FAIL)

Time/cost consuming

Use of animals

LAL

Detect only endotoxin

False positive results

Risk of interference →LER

..to a QbD-based approach for pyrogenicity evaluation:

MAT (Monocyte Activation Test)

23

ATP definition for evaluating the pyrogen content of Bexsero

Project Attribute Version PDVS Stage

Bexsero Pyrogen content 01 Life-cycle management

Sample Intended Purposes of Measurement Scope Category Output (ICH group)

Finalcontainer

Quantitatively measurement of intrinsically pyrogenic components (both endotoxin and non-endotoxin) in the drug product

Measure a quality attribute (safety)Not applied on stability

Quantitative test for safety attribute

– Based on the human reaction to pyrogens– Quantitative in vitro test– Specific for both endotoxin and non-endotoxin

pyrogens– Low variability with high sensitivity and

accuracy– No animal use (in line with 3Rs)

Monocyte Activation Test (MAT)

Implementation of MAT as pyrogen test for Bexsero in replacement of both RPT and LAL allowed a better evaluation of vaccine pyrogen content (CQA) together with a reduction of animal use

and lead-time for lots testing and release

24

Implementation of MAT as pyrogen test for Bexserorelease

MAT results for a representative

set of Bexsero batches

Approval of MAT applied to Bexsero

by International regulations

Sara Valentini, Giovanna Santoro, Federica Baffetta, Sara Franceschi, Marilena Paludi, Elisa Brandini, Leonardo Gherardini, Davide Serruto, Barbara Capecchi, «Monocyte-activation test to reliably measure the pyrogenic content of a vaccine: An in vitro pyrogen test to overcome in vivo limitations «, Vaccine 14 (2018) https://doi.org/10.1016/j.vaccine.2018.10.082

Outline

25






vaccines

Challenges & Opportunities for QbD- driven

analytical strategy

26

For vaccines, product/ process requirements are defined/ refined over time with consequent need to change ATP and, potentially, selected methods

• Optimization is ensured through screening of orthogonal methods whenproduct/ process requirements are under assessment

• Extensive characterization efforts are needed since early development to achievefit- for purpose and up-to-date analytical strategy.

After consolidating product / process requirements (eg typically in late development/ commercial phase), with a final/fixed ATP, it is important to have the best testingapproach for vaccines at any stage of life cycle

• It is important to continuously challenge and update analytical technologies with the support of ATP

How ICH Q14 and ICH Q2 (R2) could support modern

and robust analytical strategies for vaccines

27

• An ICH framework for Analytical Quality by Design would foster rigorof analytical testing strategy, focused on patient needs.

• The introduction of the concept of Analytical Target Profile (ATP)would provide scientific rationale to method selection and continuedscreening/ update, in order to ensure the best analytical strategy

• The use of ATP expectations to define critical method parameters andranges, as well as to set procedure validation criteria would ensureperformance verification based on method purpose, and not on theused technology

How ICH Q14 and ICH Q2 (R2) could support modern

and robust analytical strategies for vaccines

28

• Analytical Target Profile would support method optimization/ updatesto ensure introduction of innovation

• Application of QbD priciples/ risk- based approaches to methoddevelopment ensures the establishment of robust and well-understood analytical procedures, with reduced risk of failure forvalidation and operation, as well as sound bridging approaches

• The increased clarity in the analytical drivers and approaches couldsimplify the regulatory framework for analytical lifecycle

Acknowledgement

▪ Barbara Capecchi

▪ Francesco Norelli

▪ Sabine Leclercq

▪ Sara Valentini

▪Walter Hoyer

▪ All the other colleagues mentioned in the cited articles

29

Bexsero is a trademark of the GSK group of companiesThis work was sponsored by GlaxoSmithKline Biologicals SA

Cristiana Campa is an employee of the GSK group of companies

Questions

30

▪ How relevant are these considerations for products different from Vaccines?

▪ Is it worth dedicating specific reflection for ICH Q2/Q14, in particular on theelements below?

o Prospective and retrospective definition and use of ATP, with examples ofcompiled ATP

o Reference standard management

o Introduction of analytical innovation any time during product lifecycle

o (No) impact on specifications in case of changes of methods, under thefollowing conditions:

✓ Use of specifications as input for ATP✓ Selection/ bridging of methods based on ATP requirements

Back-ups

What is a Vaccine Product ?

32

Antigen(s) Adjuvant Administered

Vaccine

• Complex and multiple antigens

• Different structural features and doses

• Needed for specificity of the immune response

• Aluminum salts or Adjuvant Systems

• Enhance and modulate immunogenicity of the vaccine antigen

• All components in an appropriate buffer

• Potential reconstitutionbefore administration

• Vial or syringe(formulation, patientneeds)

+

33

Method replacement example- Bexsero pyrogenicity

Bexsero is indicated for active immunisation against invasivemeningococcal disease caused by Neisseria meningitidis group B.

It is a suspension for injection in pre-filled syringe, with thefollowing antigens adsorbed on aluminium hydroxide

▪ Recombinant Neisseria meningitidis group B NHBA fusionprotein

▪ Recombinant Neisseria meningitidis group B NadA protein

▪ Recombinant Neisseria meningitidis group B fHbp fusionprotein

▪ Outer membrane vesicles (OMV) from Neisseria meningitidisgroup B strain NZ98/254

34

MAT applied to Bexsero (intrinsically pyrogenic vaccine)

▪ proved to be a sensitive, specific, reproducible in vitro test suitable for routine use and for replacing the canonical animal-based pyrogen tests in the release panel of Bexsero (alignment with 3Rs), and in compliance with the Analytical Target Profile.

▪ MAT values correlate with RPT (Temperature increase) and LAL (Endotoxin content).

▪ MAT was successfully submitted and approved by different jurisdictions around the world.

MAT applied to non-pyrogenic products (generic MAT)▪ developed following Eu.Ph. Guidelines (limit test for safety attribute)

▪ based on cryo-preserved PBMCs as cell source

▪ ready to be suited as single assay to monitor both endotoxin and non-endotoxin pyrogens at release.

MAT can be developed either to quantify the amount of intrinsic pyrogenic compounds or to assess the absence of exogenous pyrogens:

Method replacement example- Bexsero pyrogenicity

Analytical methods used for process understanding may have different requirementswith respect to those used for release/ stability testing,

although they can be applied to the same CQAs

For instance, process «screening» assesses the Process Parameters criticality (i.e., variation of CQA(s) upon changing PP value), not the evaluation of the impact of the change on product quality within specifications (which is the aim of «mapping» studies)

Therefore the typical desired features for methods used for screening studies are- High throughput (to support multivariate studies and to efficiently monitor process)- High precision (to ensure reliability of assessed CQA changes due to PP changes)- High selectivity for complex matrices (to execute testing as close as possible to the investigated step)

ATP for a CQA can incorporate different applications (release/ staibility or process testing),and can potentially be associated to more than one method, if the release/ stabilityapproach is not fully suited for all applications (worse case scenario)

Process Understanding and the ATP

3535

Method parameters

(ATP requirements for

performance)

Colorimetric sialic acid HPAEC-PAD with CarboPac PA1HPAEC-PAD with CarboPac

PA20Fast

Obtained value ATP requirement Obtained value ATP requirement Obtained valueATP

requirement

Selectivity / Specificity

(Able to discriminate

analyte from matrix

signals)

Analyte not separated

from other

components;

ultrafiltration needed

for complex matrix

phases

Met upon sample UF

Analyte peak

separated from

the other matrix

components

Fully met, no UF

Analyte peak

separated from

the other matrix

components

Fully met, no

UF

Accuracy

(80-120%)

82-100%

(pre-validation data)Met

97-108%

(pre-validation

data)

Met95-99%

(validation data)Met

Precision

(CV < 8%)

2-10%

Possible variability

between different

lots and analyses

performed in long

different time (pre-

validation data)

Not fully met

CV 3-10%

(pre-validation

data)

Not fully metCV 3%

(validation data)Met

Product development stages

Case study: Group B Streptococcus glycoconjugate- saccharide content

F. Merangolo, S. Giannini, M. Gavini, S. Ricci, C. Campa, LCGC Applications of Ion Chromatography (2015) 36

Process Understanding and the ATP

Method development including QbD elements

S. Orlandini, S. Pinzauti, S. Furlanetto: Anal. Bioanal. Chem. 405 (2013) 443-450

Analytical Target Profile &

method selection

Quality Risk Assessment

Knowledge SpaceInvestigation by DoE

Design SpaceResponse Surface Metodology

Method Control

Working PointsRobustness

37

L. Nompari, S. Orlandini, B. Pasquini, C. Campa, M. Rovini, M. Del Bubba, S. Furlanetto, “Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine”, Talanta, 178 (2018) 552-562

Case study: Quality Risk Assessment (QRA) - UPLC for % adsorption of protein on an aluminum surface

Ishikawa diagram (fishbone) for screening the method parameters andfor identifying the critical process parameters (CPP) to be furtherstudied by DoE.

Screening study of the effects of chromatographic parameters onchromatographic performances


3838

287-

953

Por

B

Por

A

936-

741

961c

AU

0,00

0,10

0,20

0,30

0,40

0,50

0,60

0,70

0,80

0,90

1,00

1,10

1,20

1,30

Minutes

3,00 3,10 3,20 3,30 3,40 3,50 3,60 3,70 3,80 3,90 4,00 4,10 4,20 4,30 4,40 4,50 4,60 4,70 4,80 4,90 5,00 5,10 5,20 5,30 5,40 5,50 5,60 5,70 5,80 5,90 6,00

Pro

tein

I

Pro

tein

II

Pro

tein

III

Pro

tein

V

Pro

tein

IV

Case study: knowledge space- UPLC for % adsorption of protein on an aluminum surface


Asymmetric matrix (based onFree-Wilson model) forinvestigation of the KnowledgeSpace (KS) and to obtainpreliminary information on theeffects of the factors on methodperformance (eg peakresolution and area).

Re

solu

tio

nP

rote

in I-

Pro

tein

II

3939

Case study: knowledge space - UPLC for % adsorption of protein on an aluminum surface


Investigated performance indicators

R1: Protein I – Protein II Resolution

R2: Protein II– Protein III Resolution

R3: Protein III – Protein IV Resolution

R4: Protein V – isoform Resolution

Study outcome:

Parameters impacting peak resolution and areas & best conditions found at this stage:

- Column type: C4 pore best column

- % start Acetonitrile: 34% best value based on screening studies (under verification -design space assessment)

- Ramp time: 4 or 6 min best values based on screening studies (under verification -design space assessment)

- Column temperature: 60°C best value based on screening studies (under verification –design space assessment)

A1: Protein II

A2: Protein III

A3: Protein IV

4040

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