ICGEB International Centre for Genetic

Engineering and Biotechnology

Developing
Knowledge

Vaccine production and Technology Transfer :

a remote course for DCVMN

Module 6 :
Quality by Design and Critical Control Elements

Thomas Chattaway, CMC Consultant

[Link]@[Link]
 Outline
• The General Framework of QbD and link to Process Validation

• Critical Quality Attributes and Critical Process Parameters

• Group Exercise : Screening for CPPs

• Building a Control Strategy

• Quizz

• Group Discussion : Implications for Technology Transfer

• Reading / Assignment / Q&A

 Regulatory and Guidance Background
• Quality by design guidelines ICH Q8, Q9, Q10, Q11
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALCONFERENCE ON HARMONISATION
INTERNATIONAL OF TECHNICAL
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMANFOR REGISTRATION OF PHARMACEUTICALS
USE FORFOR
REQUIREMENTS HUMAN
REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
USE INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

PHARMACEUTICAL CGMPS ICH HARMONISED TRIPARTITE GUIDELINE ICH HARMONISED TRIPARTITE GUIDELINE ICH HARMONISED TRIPARTITE GUIDELINE ICH HARMONISED TRIPARTITE GUIDELINE
ST
FOR THE 21 CENTURY —
A RISK-BASED APPROACH
DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES
FINAL REPORT PHARMACEUTICAL DEVELOPMENT QUALITY RISK MANAGEMENT PHARMACEUTICAL QUALITY SYSTEM (CHEMICAL ENTITIES AND
BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES)
Q9 Q10
Q8(R2) Q11

Current Step 4 version Current Step 4 version Current Step 4 version Current Step 4 version

dated August 2009 dated 9 November 2005 dated 4 June 2008 dated 1 May 2012

Department of Health and Human Services

U.S Food and Drug Administration

September 2004

This Guideline has been developed by the appropriate ICH Expert Working Group
and has been subject to consultation by the regulatory parties, in accordance with the
This Guideline has been developed by the appropriate ICH Expert Working Group
ICH Process. At Step 4 of the Process the final draft is recommended for adoption to
and has been subject to consultation by the regulatory parties, inthe
accordance
regulatory with
bodiesthe
of the European Union, Japan and USA. This Guideline has been developed by the appropriate ICH Expert Working Group
ICH Process. At Step 4 of the Process the final draft is recommended for adoption to and has been subject to consultation by the regulatory parties, in accordance with
the ICH Process. At Step 4 of the Process the final draft is recommended for

• Recent Validation Guidelines, inspired by QbD

the regulatory bodies of the European Union, Japan and USA. adoption to the regulatory bodies of the European Union, Japan and USA.

This Guideline has been developed by the appropriate ICH Expert Working Group
and has been subject to consultation by the regulatory parties, in accordance with the
Annex 3, App. 7,
ICH Process. At Step 4 of the Process the final draft is recommended for adoption to WHO TRS 992, 2015
the regulatory bodies of the European Union, Japan and USA.

Guidance for Industry Annex 3

Guidelines on good manufacturing practices: validation,
Appendix 7: non-sterile process validation1
Process Validation: General
Background
Principles and Practices The appendices of the Supplementary guidelines on good manufacturing practices:
validation currently comprise the following:
Additional copies are available from: Appendix 1. Validation of heating, ventilation and air-conditioning systems
28 April 2016 21 November 2016
EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1
Office of Communications Appendix 2. Validation of water systems for pharmaceutical use
EMA/CHMP/BWP/187338/2014 Division of Drug Information, WO51, Room 2201
Committee for Medicinal Products for Human Use (CHMP) 10903 New Hampshire Ave. Appendix 3. Cleaning validation
Committee for Medicinal Products for Human Use (CHMP)
Committee for Medicinal Products for Veterinary Use (CVMP) Silver Spring, MD 20993
Appendix 4. Analytical method validation
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@[Link] Appendix 5. Validation of computerized systems
[Link]
and/or Appendix 6. Qualification of systems and equipment
Office of Communication, Outreach and Development, HFM-40
Appendix 7. Non-sterile process validation – revised text reproduced in
Guideline on process validation for the manufacture of Guideline on process validation for finished products -
Center for Biologics Evaluation and Research
Food and Drug Administration this Annex
1401 Rockville Pike, Rockville, MD 20852-1448
biotechnology-derived active substances and data to be information and data to be provided in regulatory (Tel) 800-835-4709 or 301-827-1800
[Link]

provided in the regulatory submission submissions

and/or
Communications Staff, HFV-12
Center for Veterinary Medicine 1. Background and scope 76
Food and Drug Administration
7519 Standish Place, 2. Glossary 76
Rockville, MD 20855
(Tel) 240-276-9300 3. Introduction 78
[Link]
4. Process design 80
U.S. Department of Health and Human Services 5. Process qualification 81
Draft Agreed by Biologics Working Party April 2014 Draft agreed by CHMP / CVMP Quality Working Party 2 February 2012
Food and Drug Administration
Center for Drug Evaluation and Research (CDER) 6. Continued process verification 83
Adoption by CVMP for release for consultation 8 March 2012 Center for Biologics Evaluation and Research (CBER)
7. Change management 84
Adoption by CHMP for release for consultation 25 April 2014 Center for Veterinary Medicine (CVM)

Eudralex vol 4, Annex 15

References 85
Adoption by CHMP for release for consultation 15 March 2012 January 2011
Start of public consultation 1 May 2014 Current Good Manufacturing Practices (CGMP)
Revision 1
End of consultation (deadline for comments) 31 October 2012
End of consultation (deadline for comments) 31 October 2014
Agreed by QWP 8 November 2013
BWP Drafting Group review of comments November 2014 - 1
Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006:
January 2016 Agreed by BWP 13 November 2013 Annex 4 (WHO Technical Report Series, No. 937).
75
Agreed by BWP February 2016 Adoption by CHMP 19 December 2013

Adoption by CHMP 28 April 2016 Adoption by CVMP 15 January 2014

Date for coming into effect 1 November 2016 Date for coming into effect 6 months after publication

Minor update* 21 September 2016

Keywords active substance, biologics, process validation, process evaluation,
process verification, lifecycle Agreed by QWP and IWG 21 September 2016

Agreed by BWP 5 October 2016

Adoption by CHMP 10 November 2016

Adoption by CVMP 10 November 2016

The Quality by Design Paradigm

Quality Target Critical Quality Critical Process

Inputs:
Product Profile Attributes
Materials / Process
(Drug’s URS) (of the DP or DS) Steps / Parameters

Product and Process Understanding and Design

Process Control Strategy (includes testing)

How is the knowledge built ?
(as in ICH and agency guidance)

• Combination of
• Scientific and Engineering Principles
• Data from literature or analogous professes
• Risk Analysis
• Experiments
• Process modelling

• Several approaches are acceptable

• Traditional : few variables studied, almost always by OFAT, post registration changes are
difficult
• Simple QbD : exploration of prioritised variables, combination of OFAT / DoE, post reg.
changes facilitated
• Design space : Hyperspace of variable ranges that meets CQA. Can move within.

• Flexibility
• Means and approaches can be combined in the same process (/step)
• Flexibity for manufacturing changes: in relation to the knowledge developed and data
provided
• Important for tech transfer, which is always a change in itself
Process Evaluation / QbD paradigm

From patient needs to process control limits

Risk-based
Assessments
Experimental work
Existing data,
Linking scientific
P Evaluation
clinical data to judgement
(Characterisation)
quality parameters
Identify potential
CPP (pCPPs)

CQAs inform the Product Specifications; CMAs similar assessment to CPPs ;

IPCs are directly linked to CQAs or derive from process understanding (impurity clearance)
Qbd comes with a large glossary…

• Main definitions in ICH-Q8 and Q11. Good glossary in WHO-TRS 1044

/A4 (2022)

• Quality Attributes, Material Attributes and Process Parameters are

Critical if they need to be monitored / or controlled to ensure quality :
CQA, CMA, CPP

• Process parameters have ranges associated with them - Normal

Operating or Proven Acceptable : NOR, PAR

• And many more…

The three stages of Process Validation
FDA guidance EMA guidance
WHO TRS 992, Annex 3, App7

Define
Process Design commercial Process Characterisation
Knowledge & Understanding Process Development
process
Process Control Strategy Process Evaluation

Defined Process Control Strategy

Confirm
Process Qualification effective
Facility Design – Utility Qualification
performance
Process Verification
Process Performance Qualification

Proven Process Control Strategy

Maintain
Continued Process effective On-going Process
Verification performance Verification

Maintainted Process Control Strategy

Process evaluation includes studies performed at small and/or commercial scale, to

provide evidence that the complete maufacturing process and each step/operating
unit have been appropriately designed to define the full operating ranges of the
manufacturing process (EMA guidance)
 Outline
• The General Framework of QbD and link to Process Validation

• Critical Quality Attributes and Critical Process Parameters

• Group Exercise : Screening for CPPs

• Building a Control Strategy

• Quizz

• Group Discussion : Implications for Technology Transfer

• Reading / Assignment / Q&A

Source of most of the examples used
in this module

A-VAX: Applying Quality by Design to Vaccines

CMC-Vaccines Working Group
May 2012
General Framework for Assessing
Quality Attributes of a Biopharmaceutical
Biologicals in General
QUALITY ATTRIBUTES
potency /
biological PK / PD List of attributes, from
activity
- Identity
- Structure
- Potency
Immuno-
Safety - Strength
genicity
- Variants
- Impurities
Vaccines - Stability (degradation)
- Safety
potency / - Sterility
immuno- PK / PD
genicity
- Contaminants
- Physical properties
- Presentation…

Immuno-
Safety
genicity
CQA assessment :
CMC-Vaccine Working Group Quality by Design Case Study April 2012

Polysacharide conjugated to VLP (A-Vax study)

829
830
Table 2-9: Triage Round 1 CQAs and Risk Assessment for Reconstituted A-VAX (adjuvant + Ps-
conjugate)

Quality/Product Attribute Method I* U* S*

Potency
Serotypes 1-4 (correlation) mAb-based Competitive ELISA (adsorbed) 25 2 50
Serotype 5 (no correlation) Rate Nephelometry (desorbed) 8 2 16
Animal Model (confirms correlation) Murine Serology (adsorbed) 25 2 50
Purity (desorbed Ps-VLP)
Peptidoglycan Level Calculated 8 3 24
Monomer Reducing CGE 25 2 50
Complexes/Aggregates Non-reducing CGE 25 2 50
Product-derived Impurity (desorbed Ps-VLP)
Fragments Reducing CGE 8 3 24
Complexes/Aggregates Non-reducing CGE 25 3 75
Process-derived Impurity
Activation and Conjugation Reactants Calculated 8 5 40
Structure/Function (Charac.) (adsorbed Ps-VLP unless indicated)
VLP Structure Cryo-TEM 8 5 40
Ps/VLP/Adjuvant Ratio Calculated 8 5 40
VLP Linear and Conformational Epitopes mAb-based ELISA (desorbed) 8 5 40
Ps Size Distribution HPSEC-MALLS-RI 25 5 125
Size of Aggregates DLS (desorbed) 25 5 125
Extent of Conjugation Reducing CGE 25 3 75
(as Ps-VLP, free Ps & free VLP)
Other
Quantity (as Protein Content) Calculated 25 2 50
Quantity (as Ps Content) Calculated 25 2 50
Fill Volume in Container Compendial 25 1 25
Endotoxin Compendial 25 1 25
Completeness-of-Adsorption mAb-based ELISA (adsorbed) 25 5 125
(Adsorption to Al)
Aluminum Content ICP or AA 25 1 25
831 * Impact = I, Uncertainty = U, and Severity = S (see Equation 2-1 and Table 2-7).
832
Linking CQAs to the Process
(sub-unit drug substance example)
Linking CQAs to process steps (DP, left) and to
process parameters (Bioreactors, right)
A-Mab Case Study, analogous to a sub-unit vaccine DS
 Risk Ranking to screen CPPs

Level Score Severity on CQAs

CQA respond to change in PP even within the NOR / tolerance

Very High 8
(significant effect, difficult to manage)

CQAs respond to change in PP but only if go outside outside

Moderate 4
NOR/ tolerance (significant effect, under control)

CQAs unresponsive to PP changes over a wide range (little or no

Minimal 2
effect)

Level Score Uncertainty

• Score = Severity x Uncertainty
High 3 No relevant information available; no clear rationale • pCPP iff Score > 5

Data on analogous process or from literature or highly plausible

Med 2
scientific / engineering rationale

Low 1 Data from process or strong scientific rationale

Group Exercise :Risk Ranking PPs
Example process step :
Anion Exchange Chromatography operated in Flowthrough mode, for impurity removal.
(typical in sub-unit vaccine purification, a.o.)

• Review the process information and the table in the excel file
• Rate each process parameter of the table for ‘impact’ and ‘uncertainty’ using the
grids provided (calculations are pre-programmed in excel)
• Log your main rationales (or doubts !) in the comments column
• If time : What variables would you experiment with as a result to define a control
strategy for this step ?
Go to
• Prepare a 5 min restitution Excel!
First CPP identification, provides a list of parameters that requires further data
Systematic experimental work starts… (Process Evaluation EMA guideline)

Different objectives :
• Minimum for approval or increase robustness / flexibility (Life Cycle)
• demonstrate safe operating space or wider ranges (Edge of Failure) ; Interactions
• Design space

Several experimental approaches

• Linkage studies versus Ranging studies : qualitative vs quantitative relation CQA = f (pot-CPP)
• Sequential vs Integrated ;
• OFAT (one factor at a time) vs DOE (design of experiments)

Role of modelling :
• first principles (CFD, chromatography, thermal, ‘engineering models’, statistical ; AI ?)

DOE : Design of Experiments

• Multiple factors and ANOVA
• Greater Efficiency and Robustness
• Evaluate Interactions and Curvature
• Statistical modelling : PAR determination
• Can lead to Design Space
 Outline
• The General Framework of QbD and link to Process Validation

• Critical Quality Attributes and Critical Process Parameters

• Group Exercise : Screening for CPPs

• Building a Control Strategy

• Quizz

• Group Discussion : Implications for Technology Transfer

• Reading / Assignment / Q&A

Process Control Elements

Control at Release
and….
specification, CQA GMP

Procedural Controls

In Process The 6 M’s

Controls Raw Materials
• Manpower
action limits /
acceptance • Machines
specs, CMA
criteria • Methods
• Measurements
• Materials
• Mother nature
(Environment)

Process Process Flow

Parameters Sheet
Set point, Unit ops,
ranges, CPPs sequence, size
 Raw Materials: What are we speaking about?
Different Categories / Functions Different Inherent Risks

• Drug Substance • Determines many of DP’s CQAs

• Starting materials • Genetic Stability & Integrity

• Cell banks, viruses • Infection
• Plasmids
• Chemicals • Residual Raw Materials in Drug Product
• From Simple salts to complex growth media • Source of Impurities and adventitious agents
• Processing aids and Solvents (animal origin)
• Excipients • Consistent Raw Material Quality (complex or
functional mats)

• Consumables • Degradation / Denaturation during transport or

storage
• Vials and stoppers
• Functional : resins, membranes, filters…
• Leaching of components from materials of contact
• Disposable components and assemblies
• Integrity of containers
• Levels of performance

• Security of Supply

Many of these risks require specific evaluation / studies,

some of which need repeating at Tech Transfer
Process Control Elements - Testing
• In Processs Controls (IPC)
• Checks performed during production in order to monitor and, if appropriate, to adjust the
process and/or to ensure that the intermediate or DS conforms to specification (ICH Q7).

• IPCs may allow indirect control of the process, but if implemented in a ‘closed loop’, they are
better classified as Process Parameters.
• IPCs are monitored against acceptance criteria, action limits, or using SPC approaches.

• Specifications
• A list of tests, references to analytical procedures, and appropriate acceptance criteria which
are numerical limits, ranges, or other criteria for the tests described. It establishes the set of
criteria to which a drug substance, drug product or materials at other stages of its manufacture
should conform to be considered acceptable for its intended use. (ICH Q6B)

• Specifications may apply to raw materials, intermediates and final DS / DP. Criticality of
specifications is indirectly evaluated for raw materials and DS /DP through the evaluation of
CMAs and CQAs
How to control CQAs ?

Process
• End testing is insufficient (cardinal GMP
CPPs design principle)
• End testing is not always necessary (!!),
Release
IPCs Clearanc
e studies
• Not end testing a CQA (spec) requires good
testing
justification

Measure
CQA in
intermediate
CMA the toolbox
• CQAs are controlled through a combination of
Risk process control elements
Scientific
Reasoning Analysi • Robustness (redundancy) is a key target
s • Demonstrating clearance / non occurrence may suffice

Design Validation
• The strategy must be validated (PQQ)
space

• After PQQ some IPCs may be removed and used for

CPV
• Also possible for specifications, more difficult
Linking Material, Process and In Process Controls
to DP Specification

Process
Capability

Drug Substance Specs Unit Ops

Process Limited DP Analytical
Method

Param. testing Capability

IPM & IPC DP
Specs Specs

Specs
Excipients
Stability

Nature of Mat
used in Tox &
Clinics & Dose
The Outcome : a Control Strategy
Training and Procedures

Each CQA has a ‘control strategy’:

combines testing outputs and
Raw • CMAs • CQAs End control of inputs, to ensure
Materials • Other MAs • Other QAs Testing CQA stays within acceptable limits
Process
USP, DSP, DP
Process Performance Qualification:
Process • CPPs •Quality Attributes In testing / demonstrate the Control Strategy
Design • Other PP •Process Attributes Monitoring
is effective on an appropriate
number of consecutive batches

Control of Environment
 QUIZZ

10 questions to check your understanding …

(answer yes or no)
QUIZZ Questions

# Question
1 If a product attribute is a CQA, then it has to be included in the product specification

2 All parameters in the specification are CQAs

3 It is a regulatory expectation that all vaccines be developed using QbD principles
(establishing CQAs, CPPs, a control strategy)
4 CQAs are not identified once and for all, they evolve during development and might even
be adjusted after registration
5 Yield and economic performance is relatively unimportant in quality by design and is
difficult to incorporate in the various assessments
6 Most processs parameters can be considered critical if you vary them over a wide enough
range
7 A process parameter whose change can produce a change in at least one CQA is Critical
(a CPP)
8 Control of processs parameters and final product testing are the only important elements
of a control strategy
9 Failure to meet the limits of a Specification always results in batch failure

10 Failure to meet limits of In Process Controls should trigger a deviation, but does not
necessarily lead to batch failure.
 Outline
• The General Framework of QbD and link to Process Validation

• Critical Quality Attributes and Critical Process Parameters

• Group Exercise : Screening for CPPs

• Building a Control Strategy

• Quizz

• Group Discussion : Implications for Technology Transfer

• Reading / Assignment / Q&A

 Group Discussion

What are the implications /

relevance of the QbD
methodology
on Technology Transfer ?
 Reading Support Material

• Practical exercise (on site) :

• Evaluate criticality of process or analytical steps

• Mandatory Reading (prep for Mod 7) – both given with module 6 material
• Case study Review from Module 5 (Excel File)
• List of Documents used in Tech Transfer (word file)

• Complementary Reading Matter :

• ICH-Q8 (R2) on DP/FPP or ICH-Q10 on DS/API
• WHO-TRS 1044-Annex 4(2022) : Glossary
• WHO-TRS 992-Annex 3 (2015): Validation of non sterile processes
• A-VAX study (selected parts as per interest, see TOC)
Individual Assignment TT toolbox related to
Module 5 - QbD
Contracting Regulatory
Regulatory Responsibility
Responsibility Quality
Quality Project Phases
Project Phases
Framework Framework Setting
Setting Management
Management
Framework

Scheduling// Good Product and

Scheduling the
Organising the Good Dealing with
with Product and
Controlling Organising Communication Dealing process
Controlling Interface Communication Conflict process
documentation
Tools Interface Practices Conflict
Tools Practices documentation

Knowledge Different
Different Analytical Risk
Risk Sources of
of
Knowledge information Analytical Management Sources
Management information Transfer Management discontinuity
discontinuity
Management formats
formats Transfer Tools
Tools

Identifying
Identifying ScaleUp
Scale Up TTTT Protocol
Protocol / Report
/ Report Comparability
Comparability
Training
Training (Procedure) (ICHQ5d)
(ICHQ5d)
Differences
Differences Programme
Programme (Procedure)

TTTT&&Validated
Validated
State
State
Individual Assignment

ASSIGNMENT GUIDE FOR MODULE 7

Has the process transferred to you been developed using QbD principles ? In either case, reflect
QUESTIONS on the practical consequences for the transfer (information, experiments, documentation,
training)…

Whether formally identified or not, could you pin point certain parameters, steps, aspects that
you would describe as critical and why ? Has this led to taking specific measures during transfer
or for regular production ?

Supposing you were dealing with a ‘QbD process’, what documents would you request to get the
best idea of the Control Strategy of the Process

On balance, which is the easiest process to receive : one developed without QbD, or one
developed with Qbd ? Give the pros and cons

The purpose of these questions is to stimulate reflection on the material presented in the module and on your case study. You
will find them more or less relevant to the latter, so not all should be inclued in the presentation of your case.
BACKUP SLIDES
 OUT OF SPECIFICATION

DEFINITIONS: Out Of Specifications

- OOS when a result is encountered that does not conform to the
specifications predefined by the customer or by the reference standards.
- AR (Atypical Result) means an analytical result that constitutes an
outlier compared to a trend identified for a dataset (as for Stability
Studies, for example).

References:

§ EUDRALEX Volume 4 - The Rules Governing Medicinal Product in the European Union, volume 4 – EU Guidelines to Good Manufacturing Practice Medical Products
for Human and Veterinary Use, Parts I, II, and III

§ MHRA “MEDICINE AND HEALTHCARE PRODUCTS REGULATORY AGENCY” “Out of Specification & Out of Trend Investigations” Feb. 2018
OOS Procedure _BDU

OOS- procedure
available for
discussion on-
site
OOS Procedure _BDU
 OOS EXAMPLE

[Link]