Method PubertyAdenovirus quantification CZE method implementation challenges

Lars Geurink and Ewoud van Tricht

Janssen Vaccines and Prevention, the Netherlands

Melinda, Goddess of HealingMelinda’s artwork reflects her journey living with HIV.

R&D of vaccines against: Ebola, RSV, HIV, polio, influenza

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Why?

Cell and VirusBank

Bioreactor

Cell lysis

DNA removal

Clarification Dia-filtration

Sterile filtration

Filling

Process hold

150 MDa

90 – 100 nm

dsDNA

AEX-filtration

3 days 3 h?

3.5 min

3

Why?

Cell and VirusBank

Bioreactor

Cell lysis

DNA removal

Clarification Dia-filtration

Sterile filtration

Filling

Process hold

150 MDa

90 – 100 nm

dsDNA

AEX-filtration

3 h

3.5 minTalanta, Volume 166, 1 May 2017, Pages 8–14

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Method transfer sites

-Process development

-Process Development-Analytical testing nonQC-QC

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Puberty?

Method life time

Met

ho

d p

erf

orm

ance

Met

ho

d c

on

tro

l

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Method transfer preparation

Mother natureMachine

Method installation

Material

Measurement

Men Methods

Controls

Chemicals

Consumables

Operators

Training

Skills

Knowledge

Co-validation

System suitability control

Capillary electrophoresis

Glassware

Analytical balance

Sonification bath

BSL II lab

Internet connection

Pressurized nitrogen

Temperature controlled

Trending

Issue log

Recurrent meetings

Intensive care

New Scopes

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Method transfer preparation

8

Training

Trouble-shooting

CE practice

Method practice

Software practice

CE

theory

CE best practices

Instrument theory

Set up best practices

Software theory

Trending - Critical method performance parameter

System suitability test based on risk assessment

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CMP Potential failure effect

Potential failure mode I P D RPN Mitigation I P D RPN

Reference material storage

Accuracy The RM degrades. Test articles are overestimated because the RM has contains less of the component than determined resulting in a lower signal.

9 6 9 486 Store RM at <-65 °C controlled freezer

9 2 9 162

Reference material storage

Accuracy The RM degrades. Test articles are overestimated because the RM has contains less of the component than determined resulting in a lower signal.

9 6 9 486 Trend peak area

9 6 3 162

Sum 9 2 3 54

DevelopmentImplementation

Trending – example

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External pipetting training

Internal pipetting alignment training

Changed to P1000Instead of P200

Changed back to use the P200

Instrument preparation

Solution preparation

Sample preparation

System suitability

testing

Sample testing

Data interpretation

Reporting

Issue log

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Any error, delay, obstacle on the way Log issue

KPIsCI

Problem solving

FMEA

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Cumulative method down time

0

2

4

6

8

10

12

14

16

18

Tota

l do

wn

tim

e [

h]

Solution

Problem solving

Capillary quality

Bad cut

Breakdown before first run

Heat and condense in summer

Environment lab repeatability

Missing vials stop sequence

Pressure systems

1) Cleaning

2) Reinstallation pre-puncher electrodes

3) Replacement of pressure lines

4) Handling of pressurelines during cleaning

Instrument badly manufactured (1y)

Problem solving

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Performance

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0

5

10

15

20

25

30

35

0

200

400

600

800

1000

1200

1400

1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7

2015 2016 2017 2018

Nu

mb

er o

f ru

ns

Nu

mb

er o

f sa

mp

les

Samples

Runs

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

18

20

1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7

2015 2016 2017 2018

Nu

mn

er o

f is

sues

Do

wn

tim

e [h

]

Date

Downtime (h)

Issues

DS/DP QC

New purposes? – Poster 108

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IPC AEX eluate

DB interaction

IPC BCH IPC QC

DS/DP

Serotypes

DS/DP stability

DS/DP routine

Higher sensitivity

CrudeCrude routine Seed release QC

New purposes

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CZE adenovirus

GMP

IPCGMP

DS/DP R&S

GMP

Virus seed R

IPC

Process development

support

Formulation development

supportDSP/DP characterization

New serotypes

Stability of process

intermediates

Clogging of AEX filtration

Adenovirus Domipheninteraction

Triton X-100 replacement

QC

Development support

Investigation

New purpose installation

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Investigation

Explorative question

Just do it

Development

support

Test feasibility

Optimize method

Test performance

Adjust procedure

Train operators

QC

Use development support knowledge

Change control

Train operators

Qualify method

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Method installation preparation

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Implementation statistics (3 years)

20 operators

8 instruments

2 software packages

7 application

5 investigations

6 locations

2 invalids

500 $ saved per analysis

3 h instead of 3 days

15000 samples

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Future

> +10 operators

Any instruments

All on Empower

3 locations

No recurrent issues

Continuous improvement culture

Safe, effective vaccines

▪ Special thanks to Ewoud van Tricht and Cari Sänger - van de Griend

Acknowledgement

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Talanta, Volume 166, 1 May 2017, Pages 8–14

Ph.D. supervisors

▪ Cari Sänger – van de Griend

▪ Martijn Schenning

▪ Curt Patterson

Analytical Development

▪ Harold Backus

▪ AA group

▪ Process support (PDS)

▪ QC (QCD)

PD department

Statistics

Prepare for method puberty

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