www.pei.de

CMC Strategy Forum Europe 2015

22-24 May Killarney, Ireland.

Technical innovations – impact on regulatory expectations for product

characterization

Steffen GrossHead, Section Monoclonal and Polyclonal Antibodies,Paul-Ehrlich-Institut

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

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Outline- Information in the documentation

- CTA- MAA

- Characterisation- Assay sensitivity- Setting specifications, define acceptance criteria- Clinical qualification

- Control strategy- RTRM and RTRT

- Legal requirements for testing- Monographs

Understanding of the molecule is a prerequiste forclinical trials

Characterisation of a biotechnological or biological substance (which includes the determination ofphysico-chemical properties, biological activity, immuno-chemical properties, purity and impurities) byappropriate techniques is necessary to allow relevant specification to be established. Reference to theliterature data only is not acceptable. Adequate characterisation is performed in the developmentphase prior to phase I and, where necessary, following significant process changes.

FIM/Phase I studies

5.1. Determination of strength and potencyTo determine a safe starting dose, the methods used for determination of the strength and/or the potency of the product need to be relevant, reliable and qualified.

5.2. Qualification of the material used The material used in non-clinical studies should be representative of the material to be used for FIH/early CT administration. It is important to have an adequate level of quality characterisation even at this early point of development. A characterisation of the product including its heterogeneity, degradation profile and process-related impurities should be performed.

Investigator Brochure (CTA)

MAA-Where is the information expected (hided?)3.2.S.2.6 Manufacturing Process Development

- CQA- Control strategy- Comparability

3.2.S.3 Characterisation- Structure and characteristics- Impurities (product- and process-related

3.2.S.4 Control of Drug Substance- Specifications

3.2.S.7 Stability- Stability indicating/Control strategy

3.2.P.5 Control of Drug Product

3.2.P.8 Stability

3.2.R Regional Information- Biosimilarity

Complexity of biologiocal/biotechnologicalproducts

Adapted from Carter PJ: Potent antibody therapeutics by design, Nature Rev Immunology 6, 343 (2006)

From C Siess et al, Alternative molecular formats and therapeutic applications for bispecific antibodies,Molecular Immunology 67 (2015) 95–106

New formats, potentially multiple functions

Design, generation and characterization of an anti–IL-12/IL-18 dual-variable-domain immunoglobulin DVD-Ig

from Wu et al., NATURE BIOTECHNOLOGYVOLUME 25 NUMBER 11 NOVEMBER 2007

Antibody-Drug-Conjugates

Source: Krop et al., 2010, Journal of Clinical Oncology

Source: Internet Drug index MMAE monomethyl auristatin E

Drug-load variants and isomers

2,4,6,8…

Characterisation/Specifications

Maytansinol• MayOH is a well-characterized, stable compound• MayOH is a well-defined single compound that is produced and tested for conformance against an appropriate specification using qualified reference standards.• MayOH has a well-defined and consistent impurity profile

MMAE monomethyl auristatin ESpecifications have been established based on principles outlined in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances Specifications.

Antibody SpecificationsThese specifications have to be established based on principles outlined in ICH Q6B.

The specifications set for linker and cytotoxic drug should include the recommend acceptable amounts for residual solvents guidance given in the ICH Q3C “Impurities: Guideline for residual solvents” should be followed.

-fluctuations in the manufacturing process(e.g., pH, temperature, culture media):

- changes in the manufacturing process(e.g., expression system): New product

(cell bank)

Batch inconsistency(glycosylation spectra,

aggregates)

QTPP Profile depends on the process

State-of-the-art test methods are expectedStudy Type Test System Primary Structure Amino acid sequence/composition

Molar absorptivityMolecular mass

Secondary and Higher Disulfide bond locationOrder Structure Free thiol analysis

Transition temperatures/enthalpiesInfrared absorption/vibrationsoxidation, methylation, etc.

Microheterogeneity and Charge variationPost-Translational Forms Glycan composition/structure/locationBiological Activity binding affinity

neutralization assayFcγ binding affinity

Purity/Impurity Aggregates/fragmentsResidual impurities (HCP, DNA, rProtein A)

General/Content Protein contentExcipient content

Stability Comparative long-term, accelerated and stressstability profiles

Sequence variantsBy examining the crystal structure structural predictions for the variant were made

– position is on the surface of the molecule

– variant is not predicted to impact the structure of the molecule

– variant is not expected to affect the folding of the protein

– variant is not predicted to affect the hinge region

– Position is not in a CDR, so it is not expected to affect antigen binding.

– variant does not affect the potency (91%) of the molecule using the cell based potency assay.

– variant is not in the FcRn binding region, so it is not expected to affect clearance

from Yi Yang, Alex Strahan, Charlene Li, Amy Shen, Hongbin Liu, Jun Ouyang, Viswanatham Katta, Kathleen Francissen & Boyan Zhang (2010) Detecting low level sequence variants in recombinant monoclonal antibodies, mAbs, 2:3, 285-298, DOI: 10.4161/ mabs.2.3.11718

Root cause and SolutionsIncreased method sensitivity

Correlation between cell age and sequence variant levels- Further characterization data of the variant, including functional testing- Set specification- Control variant level through cell age

Setting specifications

All features of the molecule, relevant for safety/efficiacy

Possibility to define different specifications for biologicalactivity depending on the MoA (and indication)

Binding might not be sufficient

Define pre-specified acceptance criteria

for biosimilars within the originators range but tight(justified) for process related impurities, state of the artlimits

Factor k2 for Two sided Normal Tolerance limits

Min/Max and Stability

Acceptable changes in quality attributes ofglycosylated biopharmaceuticals

Martin Schiestl, Thomas Stangler, Claudia Torella, Tadej Čepeljnik, Hansjörg Toll & Roger Grau

Differences seen in the amount of basic or acidic variants or fucosylated structures

Clinical studies with Biosimilars may provideevidence that acceptance criteria/ranges are

clinically qualified (or not)

Further implications for future manufacturing process changes if Fc function plays a role

Ask for tightening acceptance ranges, what are acceptable criteria without clinical data?

If unclear, ask for contribution of activity to overall MoA, if unclear ask for clinical studies or reject changes?

ICH Q8 (R2)• A comprehensive pharmaceutical development approach will generate

process and product understanding and identify sources of variability. • Sources of variability that can impact product quality should be identified,

appropriately understood, and subsequently controlled. • Understanding sources of variability and their impact on downstream

processes or processing, in-process materials, and drug product quality can provide an opportunity to shift controls upstream and minimize the need for end product testing.

Control Strategy

Knowledge of process performance when operated under worst-case conditions for each CQA.

Small scale studies are considered essential in order to address multivariate parameters

Provide scientific rationale for worst case All DoEs to be provided? Moving outside of worst-case conditions

The Design Space is limited by the multivariate ranges for all critical process parameters (CPPs).

DoE and Small scale studies/linkage studies

Initial ConditionsSet Points

Raw MaterialAttributes

Process variables- Equipment preparation- Manufacturing process

Performance and Quality Variables

Real-time Multivariate Statistical Monitoring (RT-MSPM)

• Need for multivariate analysis arises since most process data are complex and multivariate in nature

RT-MSPM

Historic data

RT-MSPM System

Process Control System

Monitoring Stations

Manufacturing execution systems (MES)

Laborinformations- und Management-Systeme (LIMS)

Other OfflineData

Data Integrator

ICH Q8 (R2)• Enhanced understanding of product performance can justify the use of

alternative approaches to determine that the material is meeting its quality attributes. The use of such alternatives could support real time release testing.

Control Strategy

Knowledge

Design SpaceControl

RTRT as part of a Control Strategy System of release that gives assurance that the product is of

intended quality, based on the information collected during the manufacturing process, through product knowledge and on process understanding and control

Product knowledge and process understanding, the use of quality risk management principles and the application of an appropriate pharmaceutical quality system, as defined within ICH Q8,Q9 and Q10 provide the platform for establishing RTRT mechanisms

combination of a RTR approach for certain critical quality attributes (CQAs) and a more conventional evaluation for other CQAs (partial RTR).

Where to place the controls

Pictures taken from BioProcess international

PP (CPP)IPC

DS specification

DP specificationRelease

Proposed controls

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Analyticalmethod

Drug substance Drug product

IPC Spec IPC Spec

Protein A Remove

DNA Remove

CHOP Remove

SE-HPLC Retain Retain Retain

Glycan map Introduce Remove

rCE-SDS Retain Remove

CE-HPLC As Reject Remove Remove

Good evidence of removal: Process characterization incl. interaction studies, process validation and extensive manufacturing history

Glycan pattern does not change downstream of cell culture

Orthogonal testing: SE-HPLC

”Charge profile does not change”

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Proposed controlsAnalytical methods

Drug substance Drug productIPC Spec IPC Spec

pH Retain Remove Rejection limit RemoveOsmolality Retain Remove Rejection limit RemoveProtein Conc. Retain Remove To be reported in

specificationPotency Retain RemoveAppearance Remove RetainVolume/fill weight To be reported in

specificationPolysorbate 20 Rejection limit Remove

Buffer control tested IPC

Redundant with DP testing

SE-HPLC more stab. indicating than potency

Pharmacopoeia requirementsMonoclonal antibodies for human use, 01/2012:2031

TestsAppearanceSolubilitypHOsmolalityExtractable VolumeTotal ProteinMolecular-size distributionMolecular identity and structural integrityPurityStabiliserWater/MoisterSterilityEndotoxinsTests applied to modified antibodiesAssay: carry out a suitable biological assay

INFLIXIMAB CONCENTRATED SOLUTION XXXX:2928

Product specific monographs (mAbs) Block innovation May inhibit product development May not reflect approved dossier Increase burden to industry and regulators

International Standard? Own in house standards (qualified)

Summary

Adequate characterisation is performed in the development phase prior to phase I

Advanced process analytics First principles modeling provides enhanced process understanding

and control opportunities Real-time multivariate statistical process monitoring enables proactive

monitoring of bioprocess operations, increases our understanding of raw material’s role in variation, and enables quality by design principles

Process analytical chemistry tools are important for controlling product quality and process performance

A “minimum” control system for a QbD product is considered necessary.

Legal requirements (monographs) and guidance documents for testing

Thank You!