Filing established conditions and life cycle management of a bioprocess.

9-11th May 2016: CASSS- CMC Forum

Europe 2016

Christine Mitchell-Logean UCB

■ Revenue: €3.88 billion

■ rEBITDA: €821 million

■ More than 7500 employees globally

■ Operations in ~40 countries

■ R&D Spend: 27% of revenue

■ Listed on Euronext

UCB: A Patient-Centric Biopharma Company

Stephanie, living with rheumatoid arthritis

We have a shared ambition to transform the lives of people living

with severe diseases.

We focus on central nervous system and immunology disorders –

putting patients at the center of our world.

© UCB Pharma S.A. 2016. All rights reserved.

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QBD from then to now…

The Issues • Dr.Janet Woodcock, FDA Nov.2001

• Increasing manufacturing defect trend

• Low manufacturing and QA process efficiency – cost implications

• Innovation, modernization, adoption of new technologies slowed or not adopted for US market

• High burden on FDA resources

The Responses from HA:

• PAT, QBD, ICH Q8, 9,10,11, and now 12

Today:

• Full QBD submissions are not the norm

• Mostly Approved so far without design space*

Regulatory Industry

Excessive cGMPs

More inspections,

Warning letters

Change is difficult,

innovation is risk.

Recalls, withdrawals,

supply issues

cGMP violations

More severe

enforcement

Cost / political

pressures

Persistent cGMP

violations

Regulatory Industry

Not convinced QBD

is making live easier

Cautious in

Approving QBD

(Design space)

*http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002547/WC500141004.pdf

Opposing forces ?

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Health Authorities needs: Insurance of safety, efficacy,

efficiency of resources

Industry needs: Flexibility, quick

approval, efficiency and quality

Common ground and win-win aspects

5

• Science based submission with a well characterised process that

demonstrates good understanding and a good management of risks:

• Win for HA as they are more confident that patient safety will be met

• Win for Industry as they will have less batch rejection and more flexibility.

The entire paradigm of QBD

• Still not full clear how file QBD:

• How much details to present.

• What is binding and not binding and how to file process improvements.

• Reviews of file may be reviewer dependent.

Established conditions guidance and ICHQ12 will bring value to clarify binding

and non binding information in filings.

Process development 3.2.S.2.6

6

Process

history

Comparability

of processes

CQA

Process characterisation:

• Scale down model

qualification

• DOE results: PAR

• Resin reuse

FMEA

CPP,

IPC

Control Strategy

Process Validation 3.2.S2.5

Verification of process

consistency.

CPP, IPC’s and additional

parameters monitored.

CPV, Hold times

Control of Critical steps

3.2.S.2.4

CPP

IPC with action limits

IPC with acceptance criteria

Binding

Process Description

3.3.S.2.2

Process steps information

with parameters and In-

process controls

Binding

File schematic

Specifications 3.2.S.4.1

Set of analytical tests with

define limits for CQA’s

on DS, DP and for stability

Binding

Case study of a Mab purification chromatography step

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1. S.2.6 description of development process; risk analysis, robustness studies

and control strategy

2. S 2.5 description of the process validation

3. S 2.2 description of the manufacturing process

4. S 2.4 description of the controls

5. Management of changes

2.6 Process characterisation of chromatography step

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Based on FMEA, the parameter to be studied were prioritized and tested.

Parameter Range Studied PAR Impact on

Load pH 7.5 to 8.3 7.5 to 8.3 None

Equilibration / wash conductivity

(mS/cm) 1.7 to 4.5 1.9 to 4.5 None

Equilibration / wash pH 7.5 to 8.3 7.5 to 8.3 None

Load conductivity (mS/cm) 1.7 to 4.5 1.7 to 3.6 HCP, Protein A

ligand

Load Challenge (g mAb / L resin) 30 to 60 30 to 60 None

Nb of cycle 100 100 None

Peak collection end point 0.3 to 0.7 0.3 to 0.7 None

3.2.S.2.6 CPP determination: significant* impact on

CQA

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Impact on HCP and on Protein A ligand

for load conductivity.

Assessment value:

25U/mg for HCP

1ppm for protein A ligand

PAR : Load conductivity

≥ 1.7 (limit of experimentation)

≤ 3.6 (limit of failure)

NOR: Based on equipment capability

≥ 2.6

≤ 3.6

Control:

Parameter: Load conductivity is a CPP (PAR 1.7-3.6)

IPC: Endotoxin, Bioburden, Yield

Monitoring: process impurities

* significant: with regard to analytical

variability and relevance with regards

to specification range.

3.2.S.2.5 Process validation of chromatography step

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* Will be defined after sufficient batches are manufactured

Parameter Criteria Range Run 1 Run 2 Run 3 Status

Load conductivity

(CPP) (mS/cm)

NOR 2.6-3.6 3.2 3.2 3.2 Pass

PAR 1.7-3.6

IPC Criteria

Yield (%) Action limit ≥ 85* 99 99 98 Pass

Endotoxin (EU/ml) Action limit ≤ 2 < 0.03 < 0.03

< 0.03

Pass

Bioburden (cfu/10ml) Action limit ≤ 50

0 0 0 Pass

Asymmetry Action limit 0.6-2.0 1.3 1.3 1.3 Pass

HETP Action limit >2000 2615 2373 2592 Pass

Aggregates Monitor n/a 0.4 0.4 0.4 n/a

HCP Monitor n/a 2 2 4 n/a

Beta-Glucans (ppm) Monitor n/a 0.77 1.12 1.18 n/a

Protein A (ng/mg) Monitor n/a <1 <1 <1 n/a

DNA (pg/mg) Monitor n/a ≤8 ≤4 ≤16 n/a

3.2.S.2.5 Process Validation considerations

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Control elements explained in 2.6 should be included in the validation:

• CPP (NOR and PAR are typically added to demonstrate control)

• IPC (limits are defined based on specification and process clearance)

• Additional parameters such as process impurities that may not be

measured long term should be monitored. These may be monitored for a

few additional batches beyond validation to confirm clearance with

additional data.

3.2.S.2.2 Manufacturing Process description

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* limit to be confirmed after 30 batches

Parameter Type Range values (defined by)

Column height PP x-y (Based on early experiments)

Loading capacity PP x-y ( Limit of testing)

Nb of Cycle PP x-y (Limit of testing)

Volume of equilibration buffer PP x-y (Based on early experiments)

Equilibration: buffer pH PP x-y (Limit of testing)

Equilibration: buffer conductivity PP x-y (Limit of testing)

Load: conductivity (controlled at

previous step)

CPP 1.7-3.6 (limit of testing)

Load / wash: flow rate PP x-y (Based on early experiments)

Elution: start peak collection PP x-y (Based on early experiments)

Elution: end peak collection PP x-y (Limit of testing)

IPC Type Range

Bacterial endotoxins (product pool) IPC (AL) ≤ 2EU/ml

Step yield (product pool IPC (AL) ≤ 85 %*

Bioburden (product pool) IPC (AL) ≤ 50 cfu/ml

3.2.S.2.4 Control of critical step: chromatography step

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Parameter Criteria PAR

Load: conductivity CPP 1.8-4.5

IPC

Bacterial endotoxins (product pool) IPC (AL) ≤ 2EU/ml

Step yield (product pool IPC (AL) ≤ 85 %*

Bioburden (product pool) IPC (AL) ≤ 50 cfu/ml

2.2 Process description and 2.4 control of critical step

considerations

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Enough details should be presented to describe the step

■ Parameters that were not CPP had to be included.

■ Level of details and parameters to be presented were defined based on what seemed necessary to

describe the step adequately.

■ NOR were presented when PAR were not available for parameters that were not studied.

■ The FMEA prioritize the parameters that need to be studied and thus the ones with PAR.

■ Buffer compositions are also part of the process description.

Parameter

• Process parameter: input of the process that may have defined and/or NOR

• CPP: Input parameter that if varied can have an impact on a CQA and thus should be controlled

or monitored.

IPC:

• Action limit: Either the IPC is adjusted to bring the parameter within the limit or an appropriate

action is taken and processing is continued.

• Acceptance criteria: must be met to ensure that the product is conform to its specification and

critical quality attribute

3.2.S.2.2 Change to a parameter 15

2.2 Change to IPC

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ן The difficulty for reporting lies often with the parameters that are not

specifically studied and not prioritized during the risk assessment,

but still need to be described in the manufacturing processes. A

good justification needs to be available to explain why these are not

critical.

ן The level of details to be filed in the manufacturing description is

somewhat subjective.

ן For the DOE parameters where co-dependency has been

demonstrated a change in one parameter may have an impact on

ranges of another.

This needs to be evaluated carefully if a full design space has not

been validated.

Conclusions: touchy points

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Process development S2.6

18

Process

history

Comparability

of processes

CQA

Process characterisation:

• Scale down model

qualification

• DOE results: PAR

• Resin reuse

FMEA

CPP,

IPC

Control Strategy

Process Validation S2.5

Verification of process

consistency.

CPP, IPC’s and additional

parameters monitored.

Hold times

CPV

Control of Critical steps

S2.4

CPP

IPC with action limits

IPC with acceptance criteria

Binding

Process Description S2.2

Process steps information

with parameters and In-

process controls

Binding

Established conditions

Specifications S4.1

Set of analytical tests with

define limits for CQA’s

on DS, DP and for stability

Binding

Thanks! Elaine Harris

Jennifer Halley

Vanessa Auquier

Laurence Vroye

Jonathan Monck

Mareike Harmsen

Richard Jones

Ansah Kwame and many others