European Regulatory Experiences and Expectations of HCP ...

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

18

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

19