european regulatory experiences and expectations of hcp
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www.pei.de European Regulatory
Experiences and Expectations
of HCP Analysis and Control
Part II Monoclonal Antibodies
Jörg Engelbergs
January 2015
Disclaimer:
The views presented here
are my own and do not
necessarily reflect
the official views of the
Paul-Ehrlich-Institut
or any other European
regulatory body / EMA
HCP Strategy Forum, Washington DC, January 26, 2015
Road Map
HCP control strategy during clinical development up to MAA
• Strategies for risk minimization due to rHCP
• Process capacity for HCP elimination
• General rHCP Assay development
• Setting of rHCP routine release specification and safety limits
• rHCP control strategy when applying platform manufacturing (mabs)
• rHCP routine testing versus validation studies (“out validation”)
• Use of generic versus process-specific (in-house) rHCP assays during
clinical development up to MAA
Consequences of process changes for rHCP detection
Take-Home messages
2
Safety risks Safety risks Safety risks
Strategies for risk minimization
safety
risks
regulatory requirement: production of safe biotechnology products with
regard to risk of residual HCP >>>
carefully risk analysis / discussion immunogenicity is related to nature of production host cell:
bacteria >yeast >animal cells (e.g. CHO)
patient population (immunosuppressed?)
route of administration (s.c. vs. i.v.)
maximum dose to be given to patient / frequency of application (-> indication)
safety signals from non-clinical and clinical data
powerful purification process, detection assay and control strategy
manufacturing process ->
control strategy ->
HCP assay ->
-> high capacity of HCP elimination
-> routine release specification
and/ (or) IPC testing setting
-> process-specific, highly
sensitive and specific /
good coverage of potential
HCP species 3
Process capacity
Case study
Regulatory concerns are currently very rare
mature purification process for mabs, manufacturing platform
technologies
Case: Phase I CTA: High HCP levels high in phase I clinical batches: 400-500 ng/mg
Regulatory assessment
Risk evaluation >> Indication: autoimmune disorder
HCP assay evaluated as suitable (process-specific assay)
Accepted for phase I > regulatory recommendation for phase II:
Optimizing the polishing step of downstream processing
otherwise rejection of a CTA for phase II
Following phase II CTA was accepted because:
Modification of the downstream process:
Comparable DS / IMP
HCP levels in post-change clinical batches: 40 ng/mg
Several analytical methods in use
no mandatory method is regulatory defined
suitability to be justified
however: current “gold standard”:
ELISA immunoassay (polyc. abs)
capable to detect a broad spectrum of HCPs with different pI
sensitivity in the range of HCP remaining after purification process
critical: may not detect low or non -immunogenic HCPs
new general EP monograph on HCP assay is being drafted: focus on ELISA
new orthogonal technologies (e.g. Mass Spectrometry / proteomics) may
overcome detection limitations by ELISA and my be complementary to ELISA
MS during characterization studies (identifying single HCPs)
actual less regulatory experience available (not implemented in reg. submissions)
If implementation foreseen as release test during clinical development:
recommended to discuss suitably with the national Agencies (scientific advice)
Hoffman (2000)
BioPharm 13: 38-45
5 5
HCP Assays
ELISA: Carefully characterization required
Regulatory focus: carefully characterization
demonstration of sufficient coverage of potential HCP species
CAVE! Critical if using a generic / commercial assay
current standard: 2D SDS-Page of HCP pools versus corresponding
Western Blots with anti-HCP antiserum
addressing potential HPCs co-purifying with the mab
Submission of summarized characterization data including anti-HCP antiserum
generation (if process specific assay) and discussion of achieved coverage with
respect to safety
suitability of the assay – esp. if it is a generic/commercial assay –
to be justified and demonstrated by data from clinical phase 1 on!
(several case studies for CTA with missing data > GNAs!)
Future: new expression systems upcoming (e.g. transgenic plants/ tobacco)
development of process-specific assays required
Challenge: unknown HCP impurities: carefully characterization
HCP Assays
ELISA: Carefully characterization required
6
Control strategy
Safety limits are case by case decisions
no upper safety limits for HCP impurities are regulatory defined
CPMP/BWP/382/97 - Position statement on DNA and host cell protein impurities, routine
testing versus validation studies (1997)
impossible to set a common limit of HCP
Center for Biologics Evaluation & Research - Points to Consider in the Manufacture and
Testing of Monoclonal Antibody Products for Human Use. FDA (1997)
below detectable levels using a highly sensitive analytical method
regulatory scientific justification
qualitative & quantitative HCP pattern dependents strictly on the individual
manufacturing process
host cell, fermentation system, purification process
process capability
consequently standardization of HCPs assays is problematic
reagents are product-specific
safety factors are multi-factorial
risks related to quality and clinical parameters
7
Control strategy
Safety limits are case by case decisions
no upper safety limits for HCP impurities are regulatory defined
regulatory consequences
regulatory evaluation of HCP specification limit (in ng/mg drug substance) as proposed
by the manufacturer is performed on a case-by-case basis
CAVE! limits should be carefully justified -> including a risk evaluation
safety limits discussed in the scientific community
upper impurity limits for HCP content: ≤ 100 ng/mg
e.g. L.C. Eaton, J. Chromatogr. A 705, 1995: 105–114J
process capability
mabs: state of the art purification may clear HCP to 1 ng HCP/mg (or less)
mab production = technically highly mature!
CAVE! process development program & HCP assay development
program should be oriented to reach / detect this range
but should be linked to risk assessment
8
Control strategy
Mab platform technology: generic HCP control?
EMEA/CHMP/BWP/157653/2007
production & quality control of monoclonal antibodies & related substances
“… Some manufacturers have gained considerable experience in the production of monoclonal
antibodies, and have developed a production strategy based on similar manufacturing processes
(i.e. using a predefined host cell, cell culture and purification process). This approach is often
referred to as “platform manufacturing”….”
“... the control strategy should be specifically demonstrated for the product and process being
registered. As a consequence, the suitability of the control strategy, demonstrated to be suitable
for the analysis of other product(s) derived from the same platform manufacturing approach,
should be carefully re-considered, as it may not be adapted to the product and process being
submitted.
…. host cell proteins (HCP), are highly dependent on the process, and the controls applied for a
given product and process may not be suitable for other products using the same platform
manufacturing (e.g. different cell substrates derived from a common parenteral cell line, similar
culture and purification conditions) ....”
9
Control strategy
Routine testing vs. out-validation
Case studies:
observed trend during clinical development phase II/III: HCP testing often removed
from the routine specification testing and argue that HCP is sufficiently eliminated by
the process
“validation approach”
guidance
CPMP/BWP/382/97 - Position statement on DNA & host cell protein impurities, routine
testing versus validation studies (1997)
for HCP a “validation approach” is principally not applicable
case by case review is proposed
Regulatory decisions:
Sponsors were asked to re-include HCP testing into release specification testing
10
case: during clinical development agreed that HCP testing can be eliminated
from the release specifications
Currently often accepted (> RTRT; QbD approaches upcoming) with the
following requirements:
use of a suitable process-specific HCP assay
HCP should be monitored permanently as part of in-process control testing
at relevant process step(s) with adequate acceptance criteria and action limits
IPC testing data should be presented in the IMPD or CTD for evaluation
process change: IPC data included in the analytical part of a comparability exercise
For MAA addtionally:
at least three validation batches (demonstration of HCP clearance)
data for at least the first ten consecutive commercial batches
11
Control strategy
Routine testing vs. out-validation
MAA: in line with the EMA position paper HCP testing is principally
part of routine release specification testing
Case study MAA: Mylotarg (gemtuzumab ozogamicin)
Refused 24/01/2008
EPAR: EMEA/CHMP/5130/2008 (public EMA document WC500070677)
Specifications
… The level of host cell proteins (HCP) is measured using a semi-quantitative
western blot assay which has been sufficiently validated.
The Applicant also performed a study with a quantitative ELISA method which
confirmed the low levels of HCP found using the western blot assay.
The Applicant provided a post-marketing commitment to implement the ELISA
method for release of the antibody.
12
Control strategy
Routine testing vs. out-validation
however in single cases EMA has accepted the elimination of HCP
from release specification testing
case study MAA: Tysabri (natalizumab)
approved 27/06/2006
EPAR (public EMA document WC500044690 )
Specifications
process-related impurities have been analyzed by clearance validation and
quantification in the active substance
as determination of HCP (NS/0) in more than 30 additional commercial scale
batches demonstrated a consistent low level of host cell protein, it was justified,
not to include this parameter in further batch testing of active substance
13
Control strategy
Routine testing vs. out-validation
HCP Assay development
Generic vs. process-specific assays
Regulatory-scientific concerns on generic assays:
may not detect relevant HCPs
host cell sub strain-specific HCPs
HCPs pattern influenced by the specific manufacturing process
EP 0784 - Recombinant DNA technology products of (01/2008)
General EP for Host-Cell Protein Assays in draft
14
current regulatory requirements
phase-adapted approach (CAVE! consider risk evaluation)
in early clinical phases, generic assays may considered acceptable
CAVE! if adequately characterized / validated
process-specific assays for phase III studies and MAA
HCP Assay development
Generic vs. process-specific assays
phase I phase II pivotal phase III
generic assays
process-specific In-House assays
CAVE! no assay change
Use of generic versus In-House HCP assays during clinical development:
MAA Post-MAA
15
HCP Assay development
Generic vs. process-specific assays
Phase III clinical trial application without a fully validated process-specific
assays are normally not approvable
Generic assays at MAA may lead to MAJOR regulatory concerns
(e.g. strict follow-on obligations)
case study MAA: Yervoy (ipilimumab)
authorized 13 July 2011
EPAR: EMA/CHMP/557664/2011 (public EMA document WC500109302)
… although the testing of clearance of host cell proteins (HCP) is sufficiently
controlled by a generic CHO HCP assay, this generic assay is not considered
the most suitable for its purpose based on the difficulties to fully demonstrate
its sensitivity and accuracy …
regulatory consequences:
Fixing an obligation
… with this respect, the applicant is asked to continue the development and
validation of a process-specific HCP assay …
16
Process changes during CTA and after MAA
Consequences for HCP detection
impact of process changes on HCP
upstream (fermentation process):
change of host cell line a/o fermentation parameters (e.g. scale-up) may
alter gene expression in the host/vector system potentially resulting in
different HCP profiles between pre- and post-change product
downstream (purification process):
modification may result in co-purifying a HCP species together with the
drug substance
regulatory consequences
suitability of the existing process-specific HCP assay (early clinical trials: generic
assay) should be re-evaluated with focus on specificity and sensitivity/coverage
regulators request in general confirmations that current HCP test
is further on suitable
comparative characterization studies (e.g. using 2D SDS Page, Western Blot or
other suitable (new) methods) may help to discover differences
17
Process changes during CTA and after MAA
Consequences for HCP detection
case studies mabs
For mabs no cases of post-change batches associated with serious safety
concerns (e.g. immunogenicity) have been reported so far by EMA
high process capability to eliminate HCP sufficiently (≤ 1 ng/mg)
often mammalian host cells are used
at MAA: process-specific HCP assays with high sensitivity and accuracy are
available
further regulatory considerations: clinical development
process a/o HCP assay changes in pivotal phase III studies are unwanted
impurity profile may not be indicative for the commercial product
process and HCP assay development (generic -> process specific)
should be finalized before entering phase III
except pivotal study safety findings may require HCP assay
improvement or optimization of the purification process
immunogenicity
a specific residual HCP critical for patient population
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Take-Home: Regulatory requirements &
challenges of HCP detection & control
HCP = process related impurity with a critical safety profile
risk evaluation is multifactorial
mab purification process: capable to eliminate HCP to 1 ng/mg or less
upper rHCP level based on safety evaluations: ≤ 100 ng/mg commonly accepted
HCP should be generally controlled by routine batch release testing
new approaches (validation approach/RTRT/QbD): case by case decisions
ELISA based HCP assay = gold standard
assay development highly challenging (immunogen preparation!)
assay must be well characterized >> to be shown: highly sensitive and
specific / sufficient coverage of process-specific HCP species
early clinical phases: generic assays accepted if characterized and validated
pivotal phase III: validated process-specific In-House assays
process changes: suitability of existing assay should be re-evaluated
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