‘New challenges for regulatory agencies
when evaluating QbD approaches within
licensing documentation’
Dr. Steffen Gross
Section Mono-/Polyclonal Antibodies
Paul-Ehrlich-Institut
Germany
http://www.pei.de
Disclaimer
The view expressed in the following is the ones of the
presenter and does not necessary express the view of
either the CHMP, BWP, EDQM or
the Paul-Ehrlich-Institut
Outline
 Flexibility in the manufacturing process, concerns of
the industry
 Process changes, impact on product quality (case
studies)
 Quality by design and GMP
 EMA/PAT (Process Analytical Technology) Team
 Non-clinical program for charcterisation
Quality by design
The Regulatory
Quality System
Quality Risk
Management
(Q9)
Quality Risk
Management
Quality
Systems
Quality by Design
(Pharmaceutical
Development)
Existing GMP
GMP’’s
Quality
by Design
(Q8)
Quality
Systems
(Q10)
Variation Regulation (EG) Nr. 1234/2008
Annex II
Classification of Variations
2. Major variations of type II shall comprise the following:
(a) Variations related to the addition of a new therapeutic indication or to the modification
of an existing one
(b) Variations related to substantial modifications of the summary of product
characteristics due to new clinical or pre-clinical findings;
(c) Variations related to changes outside the range of approved specifications, limits or
acceptance criteria;
(d) Variations related to modifications in the manufacturing process of the active
substance for a biological medicinal product;
(e) Variations related to the introduction of a new design space or the extension of an
approved one, where the design space has been developed in accordance with the
relevant European and international scientific guidelines.
(g-k) veterinary medical product or vaccine human influenza
Classification
Changes not requiring
any prior approval
Design
Space
Changes requiring
prior approval
Type IA
Type IB
Type II
Extension
Minor var.
minimal or
no impact
on Q/S/E
Minor var.
Major var.
Significant
impact
on Q/S/E
as listed in
Annex I to Reg.
(strength,
Pharm. form..)
Do and tell
Variations
Evaluation Procedure adapted to the level of risk
Variation?
Design space:
• proposed by the applicant
• subject to regulatory assessment and approval.
• it is the multidimensional combination and interaction of
input variables and process parameters.
Working within a design space
• not considered as a change
• movement out of the design space = change, which
generates a Type II Variation
Main concerns from Industry
 No “improvements” for biologicals/immunologicals
 Flexibility with regard to implementation of ICH Q8, Q9, Q10
 Advise to inform RMS/EMEA of upcoming post-authorisation submissions for the
following 6-12 months
 Typ IA – rejection by NCA – how to mitigate
 Typ IB by default – re-classification to Type II
 Grouping issues
 Worksharing issues
“The process is the product. “
-fluctuations in the manufacturing
process
(e.g., pH, temperature, culture media):
Batch inconsistency
(glycosylation spectra,
aggregates)
- changes in the manufacturing process
(e.g., expression system):
New product
(cell bank)
• „One process – one product“ paradigm
Production of monoclonal antibodies
Platform manufacturing
As for any medicinal product, the manufacturing process of a
product that has been developed using a platform manufacturing
approach should be appropriately validated at the time of
marketing authorisation application. Validation studies should
include data derived from the final manufacturing process and
site(s) used to produce the product to be commercialised.
Nevertheless, when appropriately justified and documented, data
derived from other relevant experience may be used to support or
reduce the data derived from the final commercial process to be
submitted.
Subtle changes to the structure can result in
profound effects on the activity
 complexity in specified biological molecules.
 The structure of specified biologicals is related to the
function (biological activity)
- e.g. genetic Instability of Cell Banks
- Issues within Fermentation and Purification
resulting in changes in ……
 Post Translational Modifications
 Product Degradation or Modification
resulting in differences in ……
 Purity
 Biological activities
 (Immunogenicity)
Change in manufacturing process active substance
Exampel 1
New process to increase yield and consistency;
Operational process flow and process controls identical
Change:
cell culture: working volumes, culture duration, culture media and
feed
purification: increase column loading, resins but same ligand ,
number of cycles
Documentation:
Testing of the EPC confirmed genetic stability of the cell line as well
as the viral safety
serum-free culture medium. No TSE-risk components
Process validation: clearance of process related impurities,
Consistency, Column Life time Validation, viral clearance
Demonstration of comparability according to Q5E
Comprehensive set of analytical methods
increasing sensitivity
 Physicochemical characterisation, e.g.
-
Mass spectrometry techniques (e.g., MALDI-TOF)
Nuclear magnetic resonance
Capillary electrophoresis with laser-induced fluorescence detection
(CE-LIF)
 Primary structure
-
peptide map
 Secondary structure detection, e.g.
-
Circular dichroism in near- and far-UV spectra
 Product related variants and impurities
-
SEC, CE-SDS, CZE, CEX, etc.
 Antigen-antibody interaction, e.g.
-
Surface plasmon resonance
FACS
 Combination of methodologies, e.g.
-
liquid chromatography combined with mass spectrometry
Physico-chemical charactersation
Impact on activity by posttranslational
modifications
Complex mode of actions
Activation of effector mechanisms, Immunmodulation
- ADCC
- CDC
- activation of T-cells
Targeting
Inhibition
- blocking of ligand binding
- inhibition of dimerisation, internalisation, shedding
Induction of apoptosis
Global manufacturing
process harmonization,
adaption of the manufacturing process
Process harmonisation – Example 2
afucosylated structures and ADCC
Conclusion/Action
1. The applicant commits to
 continue to better understand the observed phenomenon
regarding ADCC clustering by the investigation of afucosylation
and relative ADCC activity and the impact of depth filtration on
glycopattern and provide more information as soon as it is
available
 use depth filtration in the media preparation process at both sites
in order to improve site to site-consistency of the glycopattern
2. The following information should be submitted as FUM
 a) The afucosylation and ADCC data from the next ten batches
produced with depth filtration should be provided.
 b) The applicant is asked to screen their pharmacovigilance data
and discuss whether there might be a correlation if the number of
registered adverse events might be correlated to the source of the
used batch and therefore possibly linked to a different ADCC.
Achievement Process harmonization
Exampel 3
 several submissions in order to harmonize the
manufacturing process across different sites
 data in the dossier seem to prove the
harmonisation process
 release data did not show differences
 extented characteristion revealed (minor)
differences between sites
 detection of AE
 root cause investigation
Guideline on similar biological medicinal
products (CHMP/437/04)
• Scope: Any biological medicinal product
• Biotechnology derived protein
• Immunogicals (e.g. vaccines and allergens):
• Blood products or recombinant alternatives:
• Others (e.g. gene, cell therapy)
• "Generic approach": not appropriate to biologics due to complexity of
molecular structure and/or production
• Biosimilarity to be established at all levels: Q / S / E
• Reference medicinal product: must be authorised in the Community on the
basis of a complete dossier
Development of a biosimilar following a
QbD approach.
target definition
characterisation
Refinement
Development of a
biosimilar Product
QbD
process
development
comparability
exercise
Quality guideline (CHMP/BWP/49348/2005)
Comparability exercise versus reference product
Comparison against official data is not sufficient
Quality attributes:
-not expected to be identical.
-Limits: not wider than the range of variability of the
reference product
-Differences: to be justified in relation to safety and
efficacy.
Exampel 4
Complete quality range for
justification of limits and
claiming biosimilarity
basic variants
ADCC
„Design Space“ Concept for biosimilars
•ICH Q8, Q9 and Q10 are applicable for biosimilars
manufacturers for their own developments in the
same way as for the originators.
•A „design space“depends on a particular
manufacturing process
“The process is the product. “
characterisation of the
drug substance/drug
product
characterisation of the
manufacturing
process
Quality by Design
QbD
 A harmonized pharmaceutical quality system applicable across
the life cycle of the product emphasizing an integrated approach
to quality risk management and science
- New ICH guidelines (High level guidelines, more visionary, less
prescriptive, flexible regulatory approaches)
• Pharmaceutical Development (Q8)
• Quality Risk Management (Q9)
• Pharmaceutical Quality Systems (Q10)
Interaction assessors-inspectors
The Regulatory
Quality System
Quality Risk
Management
(Q9)
Quality Risk
Management
Quality
Systems
Quality by Design
(Pharmaceutical
Development)
Existing GMP
GMP’’s
Quality
by Design
(Q8)
Quality
Systems
(Q10)
Requirement for close interaction assessors-inspectors
Assessment: stronger focus on IPC
Reflection Paper
Involvment of experts (assessors)
today
 Covers Module 3 of CTD (common technical
document)
- Eudralex Volume 2
 In connection with Good Manufacturing Practice
guidelines
- Eudralex Volume 4, Part I and II plus Annexes (Annex 1)
Areas of special interest for experts
Master Cell Bank and Working Cell Bank
• Storage Conditions and Maintenance
• Verify that the written procedures reflect accurately what is
submitted in the application
• Determine that batch records follow written procedures
• Determine the identity and traceability of the MCB/WCB
• Check the conditions of storage at each location
• Check the accessability to MCB and WCB
• Document any samples of the MCB/WCB that failed to meet all
specifications
Cell culture and fermentation
 Inoculation and Aseptic Transfer
- Handling of cells, equipment in the inoculation area
 Monitoring of Growth Parameters and Control
- Review cell growth records (e.g. IPC)
 Contamination Control
- Review written procedures to determine what investigations and
corrective actions
Extraction, Isolation and Purification
 Adequate descriptions and specifications for all equipment,
columns, reagents, buffers and expected yields.
- In-process controls
 Process validation
-
Column life time and labelling
Re-processing steps
Holding times
Sampling, delivery of samples to QC
 Cleaning procedures to avoid cross contamination
Laboratory controls (1)
 Training
- Laboratory personnel should be adequately trained for the jobs
they are performing
- Training records; e-learn systems
 Equipment Maintenance/Calibration/Monitoring
- documentation and schedules for maintenance, calibration, and
monitoring of laboratory equipment.
 Method Validation
- Firms should have raw data to support validation parameters in
submitted applications.
Laboratory controls (2)
 Standard/Reference Material
- Reference standards should be well characterized and
documented, properly stored, secured, and utilized during testing
- Storage of reserve/retain samples
- Qualification of standards
 Critical reagents
- Laboratory cultures and reagents, such as enzymes, antibodies,
test reagents, etc.
 Laboratory SOPs
- Procedures should be written, applicable and followed and
present.
Advantage of assessors
Experts know different facilities of the same MAH
-Ususally competent Land authorities inspect the same facilities
Experts are familiar with the dossier
-cell banks
-manufacturing process
including validation
in-process controls
control of drug substance/drug product
analytical methods
Reference material
Stability/shelf life
Adventage for assessors
 Experiences taken into consideration for
assessments
 Insight into the manufacturing processes
- New developments
Quality Risk
 On side discussion with the company
The Regulatory
Quality System
(Q9)
Management
Quality Risk
Management
Quality
Systems
Quality by Design
(Pharmaceutical
Development)
Existing
GMP s ’
Quality
(Q8)
Quality
Systems
(Q10)
Process improvements under the “QbD” paradigm:
 Process transfers under an expanded change protocol
in the US
 EU perspective on Expanded change protocols
EMA PAT Team
 has started its activities in January 2004
- Composition
• quality assessors for chemical products (appointed by QWP)
• GMP inspectors (appointed by the GMDP IWG)
• an observer appointed by BWP
- Activities:
• guidance documents currently published on the EMA website
• co-organised with industry training and workshops on QbD,
• Discussion/advice to several pharmaceutical companies on QbD/PAT
elements and strategies
 December 2006: mandate
- quality assessors for biological products (appointed by
BWP) were added to the team.
Problem statement
 No formal system in place for involvement
of the PAT Team with assessment of
applications and SA procedures
- team involved if there is a request from the
applicant or upon information received from
one of the EMA staff team members.
 Discussion with companies: informal
 Unclear role of the team in both
assessments of applications and SA
procedures.
 Some overlap of activities with ICH Quality
Implementation Working Group (IWG)
e.g.Q/As
Discussion
 Until this specific competence is more wide spread among
regulators, any pre-submission advice on QbD coming from
EMA is handled through the PAT Team.
 Advice on QbD/PAT: possibility to obtain a more formal
outcome.
- should be handled through the existing Scientific Advice
procedure,
- but a draft report by the team and subsequently adopted by
BWP, GMDP IWG and/or QWP as relevant and CHMP/CVMP
 Broader scientific advice that includes QbD aspects:
- normal scientific advice procedure should be used
- but the procedure should be modified so that:
• the preparation of the initial recommendation on QbD matters is done by the
team, and
• successively adopted by the relevant working party/group together with the other
parts of the scientific advice request.
Discussion
 Annual joint meetings with BWP, GMDP IWG and
QWP should be organised.
 Mandate should be reconsidered periodically (e.g.
every 5 years), in order to evaluate if the general
knowledge on QbD reached by assessors and
inspectors still justifies the role of the team in the
provision of scientific advice for QbD related
matters.
Proposal from the secretariat
Mandate of the group
 Organise/participate in training of assessors and inspectors as well as
pharmaceutical industry on QbD
 Routinely participate to the assessment report peer review of centralised
applications including QbD/PAT elements
 Discuss, upon request from companies, QbD/PAT overall strategies during
early pharmaceutical development phases of products
 Provide recommendation to the relevant working parties/groups/committees
in order to facilitate the provision of formal scientific advice to applicants
seeking advice in the context of QbD/PAT
 Provide, upon request from National Competent Authorities and/or applicants,
support for the assessment of applications in decentralised, mutual
recognition and national procedures on matters related to Quality by Design
and PAT
 Provide, upon request from Supervisory Authorities and/or companies, advice
on inspections/GMP matters involving QbD/PAT elements, including the
possibility of participation of PAT members to GMP inspections
 Develop guidance to facilitate the implementation of the new approaches to
quality through an integrated application of ICHQ8, Q9 and Q10 within the EU
regulatory system, also through input to the work of the ICH Quality
Implementation Working Group
Proposal from the secretariat
Composition
 core group with 23 members appointed by CHMP on proposal from the
QWP, BWP, GMDP IWG and EMA as applicable and additional experts,
individuated by QWP, BWP or GMDP IWG on an ad hoc basis to participate
to specific meetings for specific products under discussion
 Composition of the core group:
-
5 experts from QWP
5 experts from BWP
4 GMP inspectors
Chairs of the BWP, QWP and GMDP IWG
1 EDQM staff appointed by EDQM
4 EMA staff + 1 EMA staff responsible for the scientific secretariat.
 Expertise in the core group to cover, in addition to general expertise in the
field of QbD, the main specialist areas for assessment of applications with
QbD/PAT elements and related inspections, including for example, but not
limited to:
-
Chemiometrics
Mathematical models
Statistics
Near Infra Red spectroscopy
Sensors used in PAT
Application of PAT to biologicals
Biologics are threesome
Quality
Non-Clinical
- impurities
- batch inconsistency
- contaminants
- microheterogeneity
- fragments
- tissue cross-reactivity?
- toxicity?
- immunotoxicity?
BRIDGING
Clinical
- additional safety measures required?
- immunogenicity
Conclusion Quality
Current methodology sensitive to detect differences
in primary structure, identity and amount of related
variants including aggregates, glycosylation profile etc.
Major question is not the ability to detect differences
but the determination of their clinical relevance
to be answered by combining physicochemical results
with functional assays and the qualification in preclinical
and clinical studies
Understanding of signaling pathways
Source: MA W.W., Adjei A.A.; CA Cancer J Clin. 2009 Mar-Apr;59(2):111-37.
Dossier requirements
CTD Module
Originator
QbD Dossier
comparability data
Quality
Non clinical
cross reference
clinical
cross reference
(extrapolation?)
The End
Comparable?