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
➢ 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
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
➢ QbD-driven analytical strategy
➢ 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
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
➢ QbD-driven analytical strategy
➢ 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
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
Method development including QbD elements
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
Method development including QbD elements
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
Method development including QbD elements
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