mkt always applicable

Use of MKT

How To Proceed

Some knowledge sharing,

thoughts, ideas,…

Werner Stilmant

Cold Chain Specialist

LINKEDIN PROFILE Werner Stilma

nt

http://be.linkedin.com/in/wernerstilmant


Sta

rtin

g P

oin

t Pharmacuetical General Mission and Values

Highlighting following values Be Science Based

Create value for patients

Ensure quality

Variability of International Regulations

Variability in distribution settings on International level

Pipeline Clinical Trials (Antibodies / Proteins)

Temperature Monitoring and related deviations

Bench Marking

NOV 2012

Werner StilmantCold Chain Specialist

LINKEDIN PROFILE Werner Stilmant



Sco

pe a

nd G

oal

The goal is not to set a good or

bad positioning Provide helicopter view on

current strategy Assess the link between

business model and supporting

services Give insight in molecular

settings and related risk

MKT calculation and importance

Provide possible solutions or

strategies Provide a base to decide next

steps on how we proceed within

cold chain settings

NOV 2012





NOV 2012

Sco

pe a

nd T

opic

s co

vere

d

Characterization of pharmceutical cold chain

products None Arrhenius Behavior

Strategy and known risks

Use of MKT some examples

• Evaluate Excursions• Evaluate/Qualify shipping

units Some types of insulation

and their potential effect

Choices to make and their

potential result/effectWerner StilmantCold Chain Specialist




Chara

cteri

zati

on o

f in

nova

tive

pro

duct

lin

e

Protein/Anti-body Structure Primary

Secondary

Tertiary

Quaternary

Denaturation Triggered by Heat / Cold,

pressure, PH, etc.

Irreversible affected by Temperature shock

Unfolding Temperature

Irreversible reactions

Differences with small molecules

NOV 2012





Ass

ess

ing

Tem

pera

ture

Spik

es

and B

iolo

gic

als

Challenging biologocal products

Stability behavior more

complicated Other types of degradation due to

specific structure Degradation may be non-

Arrhenius, therefore MKT may not

apply Simple Freeze Thaw cycles may

not present extremes Stability behavior may be different if

thawed quickly or slowly.

Since Arrhenius may not apply

(within a temp range) short term

spikes may have an effect on long

term stability. (See slide Non-

Arrhenius behavior)

NOV 2012





Non-A

rrheniu

s B

ehavi

or

Degradation mechanism in

proteins often change with

temperature Causes Multiple reaction pathways

Change in physical form when

temperature changes

pH shifts Potential equilibrium between native

and intermediate state

Extrapolated shelf life prediction

are not always accurate due to

the above Regulatory agencies look at

stability data of proteins with

great caution; requesting often

real-time stability tests.

NOV 2012





Ass

um

pti

ons

made All curent and future

products follow Arrhenius equations

No impact analysis of different temperature spikes (shock)

“Regulatory agancies agree per definition with Pharma strategy ”? Defendable on International level ?

(ICH) required stability data sufficient to sustane strategy.

NOV 2012





Exc

isti

ng S

trate

gy

: Pr

oduct

ship

ped

outs

ide it

s la

bele

d

stora

ge r

ange

Qualification of shippers

MKT ?

Profiles reflecting

90% of shipments

Use of stability

data; allocating

time to shipments

NOV 2012





Som

e R

ela

ted

risk

sTemperature excursions• During monitored shipments• What about none monitored shipments ?

Country specific regulatory requirements• Variable within International Environment• Requesting more and more monitoring during shipping

• Considering more and more storage conditions as being applicable for shipping conditions

Every shipment being unique• By averaging you risk of ignoring worst case settings

• Difficult to defend towards agancies with growing know-how on cold chain aspects

NOV 2012





Usi

ng M

KT f

or

Qualifi

cati

on o

f Ship

pers

: E

ffect

s

Positive

Negative

Unknown real cold chain capacity of shipping boxes

New Products not matching assumptions ?

Non Arrhenius

Cost ?

Simplicity

NOV 2012





MKT

som

e

exam

ple

s “Confidential”

NOV 2012





NOV 2012

MKT

, Spik

es

and

Insu

lati

on u

sed Definition: “The ease with which heat flows through a material

is measured by its thermal conductivity. The higher the conductivity, the easier the heat flow.”

Comparing EPS with PU results it is clear that sudden changes in ambient temperatures (spikes) will be reflected more in EPS shippers.

Sudden (frequent) spikes (temp shocks) can have a negative impact on protein structure (product specific) or effect on expiry period

MKT will average this out, while chances of encountering spikes are higher

Vacuum technologies not that often used within current configurations. Potential ?





Ambient

0 – 25 °C

15 – 25 °C

2 – 8 °C

Str

ate

gic

deci

sion

wit

h lo

ng t

erm

im

pact

Acceptance of MKT for Qualification

Multiple International and growing

regulatory requirements can make

acceptance difficult when audited

Unknown actual temperature during

transit Longer qualified time for shippers

Easier to reach succesful test results

during qualification rounds

Non-Acceptance of MKT for

Qualification Use of MKT for evaluating potential

excursions Potential impact on design of shippers

More certainty towards product quality

Potential effect on developing 4 quality

levels within temperature controlled

shipments Regulatory acceptance easier to achieve

NOV 2012





Addit

ional s

lides

/ Fu

rther

Info

rmati

on

NOV 2012

Additional slides / Further

Information





Definit

ions

/ B

ack

gro

und

Note : ∆H USP refers to a generic activation energy of 83.14 kJ/mol)

NOV 2012





Refe

rence

s (1

)

NOV 2012





Refe

rence

s (2

)

• Singh, S.P. , Burgess, G and Singh , J (2008). Performance Comparison of Thermal Insulated Packaging Boxes, Bags and Refrigerants for Single-parcel Shipments. Packaging Technology and Science, 21-35.

NOV 2012





Handbook

of

Sta

bili

ty

Test

ing in

Pharm

ace

uti

cal

Deve

lopm

ent:

Regula

tions

...

Kim Huynh [email protected]

http://pharmalytik.com/

NOV 2012



mailto:[email protected]



http://pharmalytik.com/



Pharm

ace

uti

cal S

tabili

ty T

est

ing

to S

upport

Glo

bal M

ark

ets

(1)

By

Kim

Huyn

h B

a

NOV 2012





Pharm

ace

uti

cal S

tabili

ty T

est

ing

to S

upport

Glo

bal M

ark

ets

(2)

By

Kim

Huyn

h B

a

NOV 2012





Saoudi A

rabia

Regula

tions

2011

A new requirement by SFDA

[Saudi Food & Drug Authority] that: 1 - Products that stored

between 2 - 8 C, shipment

must carry TempTale Monitor

starting from Mar. 1st 2011 2 - All other products with

normal storage [ 25 C ] must

carry Temp Tale Monitor

starting from June, 1st 2011. Microsoft Office

Word 97 - 2003 Document

NOV 2012





mkt always applicable

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