optimization of industrial freeze drying cycle - two case studies · | 8 data acquisition :...
TRANSCRIPT
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Optimization of industrial freeze drying cycle - Two case studies
DDF 2019
M.Nakach
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Scope
● Context of the studies● Methodology● Product A example● Product B example● Conclusion
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Introduction : context of the studies● Redevelop a freeze drying process for internal manufacturing of :
● Two “old” products of the 60’s (called “A” and B”) performed with historical cycles in subcontract Manufacturing, to be transferred back in the company
● Historically very few process or physical chemistry data available due to the age of the products
● Pharmaceutical elegance issues for both products
● Take into account the characteristics of the target industrial machine :● 30 m² freeze dryer: 72000* 7 ml vials or 42000*15 ml vials ● Maximum sublimation rate ~10.5 kg/h mean flow (or 16 kg/h max flow) at 150
µbar, limited by hydrodynamics (shocked flow)● Capacitive pressure probe in chamber and ice trap + Pirani probe in the
chamber detection of the primary sublimation end point by pirani/capacitive pressure possible
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Scope
● Context of the studies● Methodology● Product A example● Product B example● Conclusion
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Methodology :
● The methodology was based on :● The product knowledge :
• does the product is crystalline or amorphous ? • Does annealing is an option or not ?• What is the critical temperature for the primary drying phase (Tg’, T
collapse, T eutectic) ?● The equipment knowledge :
• How does the heat transfer coefficients vary with the freeze dryer scale (lab or industrial?
• What is the maximum vapor flow that the freeze dryer can handlle?● The modeling and simulation
• The heat transfer coefficient (“Kv”) and mass transport resistance in the cake (“Rp”) are acquired at lab scale trials
• Simulations are performed in order to get optimal conditions
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Methodology : theory & parameters to measureA simple 1-D , quasi steady-state theory is sufficient to describe accurately the primary sublimation
From Steve L. Neil “ A Design Space Approach to Freeze Dry Cycle Development and Optimization “. April 2012 , Bio Pharma Solutions
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Experimental approach: Data acquisition & process optimization methodology
Experiment # 1
Experimental profiles :•Product Temperature
•Pirani/ MKS => PD end point•Condenser Tprofile ( sublimation rate approx. profile)
Freeze drying parameters : Kv, Rp(h)
Simulation of exp # 2, 3, 4 …
Final conditions
Prediction verification
Parameter fine tuning
Product characterization
Iteration loop
Lab scale : Martin Christ Epsilon 2-6 D, 2 shelfs having a total surface of 0.135 m² (270 vials), Ice capacity: 4kg/ 24 kPirani/MKS recording chamber, T shelf, T condenser, 3 product probes
The simulation allows to design experiments which should fit flow and temperature requirements
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Data acquisition : redundant information● The temperature profile is the main source of
information , however over information is available.
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Aggressive cycle
conservative cycle
Tem
pera
ture
°C
Condenser TPirani
Capacitive
Example giving, the condenser outlet temperature provides a quite accurate image of the ice sublimation (=condensation in the trap) profile.
The Pirani/capacitive probe convergence provides the sublimation end point
Coherence of information is essential
T °C
P m
bar
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Scope
● Context of the studies● Methodology● Product A example● Product B example● Conclusion
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Case study: Challenges of the Product A● Product characteristics
● No excipient are used in the formulation● Fully Amorphous product (X-rays)● Low value of Tg’ =-35°C (modulated DSC)● Very diluted solution :~ 45 mg in 1,5 ml WFI strong
collapse is possible
M-DSC : Tg’ at -35°C● Productivity challenge :
● Historical cycle was very aggressive (shelf Temperature at 50°C) many collapsed samples
● 72000 (5 ml) vials on 30 m² shelves- About 100 kg of ice to sublimate
● The whole cycle should work within 24 hours
elegant Collapsed
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Product A historical cycle
● Product A historical cycle was very aggressive : ● too quick evaporation : the machine cannot support the flow● The product temperature raised well above the Tg’ high
collapse risk
Tg’-35
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Product A: Experimental strategy
● Experimental strategy : to define the quickest primary sublimation conditions which :● Keeps low temperature (below or close to Tg’) and good pharmaceutical elegance
of freeze dried cake ● Keeps the mean sublimation rate below ~10.5 kg/h, it is < 0.15 g/h.vial● Productivity : Overall FD cycle (freezing + PD + SD ) < 24 h
Shelf temperature
Cha
mbe
r pre
ssur
e
“Hot ice” & slow
“Hot ice” & quick
“cool ice” & very slow
-15°C -5°C-25°C
140µb(Tice :-39°C)
80µb(Tice :-44°C)
#2 #3
#1
The experimental strategy was based on performing 3 trials best conditions
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Example of data acquisition- Product A
freeze drying simulationGardenal 40 - Optimisation MAF 5
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-8-6-4-202
0 2 4 6 8 10 12 14
Time (h)
T (°C
)
simul bottom T
simul ice front T
Etagère
center vial measured T
TG'
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-45
-40
-35
-30
-25
-20
-15
-10
-5
0
0 2 4 6 8 10 12 14 16 18 20
Temps (heures)
T°C
0,100
1,000
Pres
sion
(mba
rs)
T°C étagère T°C produit Pression MKS Pression Pirani
Kv ~ 10 W/m²°C (140µb)
0
1
2
3
4
5
6
0,0 0,1 0,2 0,3 0,4 0,5 0,6
Hauteur gateau sec (cm)
Rp
(Tor
r.cm
2.h/
g)
Série1
Série3
Rp = function of dry cake Low Rp values due to high cake porosity – The temperature does not increase a lot during PD-Stays close to the ice temperature at Pchamber
Probe out of ice
End of PD : pirani = MKS
Extrapolated bottom T
End of PD : pirani = MKS
extrapolated
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Results of lab scale trials
Optimized conditions : Tshelf -5°C , P= 150 +/- 10 µbars
P.Drying 12.5 -13 h
•Xrays :amorphous halo
•Pore size ~tenths of microns
•Very porous
Shelf temperature
Cha
mbe
r pre
ssur
e
“Hot ice” & slow
“Hot ice” & quick
“cool ice” & very slow
-15°C -5°C-25°C
140µb(Tice :-39°C)
80µb(Tice :-44°C)
#2 #3
#1“elegant” 0,14 g/h.vial
“elegant” 0,09 g /h.vial
“elegant” 0,07 g /h.vial
“Hot ice” & quick
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Industrial scale-up
The chamber /trap P indicates the gas flow rate
The Pirani/MKS signal indicates the PS end /point
For the first industrial trial, the transition to secondary drying is made “manually”, after Pirani came back to base line,
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Industrial scale-upFirst trial : Tshelf -5°C ,P: 150 µb P Drying : 12.5 h (similar pilot) Tmax ~-25°C
Product OK (elegance and water content)
Second trial : Tshelf 0°C ,P: 150 µb P Drying : 11.5 h (similar pilot) Tmax ~-25°C
Product OK (elegance and water content) conditions kept for validation
comparison pilot/industrial
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-10,0
-5,0
0,00 2 4 6 8 10 12 14
time
prod
uctT
°C
shelf
Lab sclae (trial 5)
f irst industrial trial
140 µbar
150 µbar
3 validation batches successfully performed
Industrial T profile very close to lab scale
The water vapor flow can be deduced from the chamber to condenser pressure drop
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Case study 2 – Product B
● Formulation product B● Pure API – no excipient● High API concentration ~28% High Rp and product heating should be anticipated● Solution height in the vial~1.4cm (vial 7mL)
● Industrial scale● 72000 vials● ~170 kg of ice to trap
● Pharmaceutical elegance was not acceptable: Many defects observed using the historical cycle~15%● Double layer, crevices x x
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Product B – basic data ● Solid form
● Partly & randomly crystalline product)
● DSC ● Tg’ @ -25°C (if non crystallized)
● Teutectic @ -3°C
Inte
nsité
(u.a
.)
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Lot #147 Lot #148 Lot #150
After annealing at -10°C no more Tg’Tg’ -25°C
The API randomly crystallizes during the freeze drying- It may recrystallize consistently when an annealing (>1/2 hour) @ -10°C is applied
But eutectic temperature = -3°C
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Product B – historical cycle
The historical cycle was characterized by a regular increase of shelf temperature
The product temperature was going over Tg’ and over the eutectic temperature and may be over 0°C
Eutectic !
!Tg’
Temperature recordings –old cycle
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Product B: Experimental Strategy
● To understand the effect of annealing on the product crystallinity (real freeze drying conditions).
● To perform a “reference” trial with the “old” aggressive cycle in order to verify that the elegance issue can be duplicated at lab. scale
● To perform a trial with or without annealing determine the highest sublimation rate :● Limiting Tp< Teutectic (in practice T< -5°C)● Compatible with the known industrial FD evaporative capacity ● Compatible with the previous “dossier” specification
● To anneal or not to anneal that is the question ?
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Reference cycle (lab trial)
● No annealing● Very quick sublimation PD~17h (Pirani) ● Tp > 0°C at the end of PD
Inte
nsité
(u.a
.)
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Lyophilisat Cycle #3
crevice
Partly amorphous
The lab trial confirms that it is possible to reproduce large scale issues : validates the use of the lab scale ( Epsilon 2-6D)
Most vials have an elegance issue
Eutectic (-3°C)
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-20
0
20
40
Tem
péra
ture
(°C
)
2520151050Temps (h)
0.2
0.1
Pres
sion
(mba
r)
Cycle #3 (Maisons-Alfort)Température (°C): Pression (mbar):
Produit - milieu MKSProduit - arrière PiraniProduit - façadeConsigne étagère
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Reference cycle – Sublimation flow
● Mean flow : 0,22g/h/vial 16kg/h full scale (72000 vials)● Max flow : 0,26g/h/vial 19kg/h full scale (72000 vials)
freeze drying simulation ancien cycle thiophenicol
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-10
0
10
20
30
40
0 5 10 15 20
Time (h)
T (°C
)
0
0,05
0,1
0,15
0,2
0,25
0,3
Flux
éva
pora
toire
(g/h
.flac
on)
simul bottom Tsimul ice front TEtagèreExperimentalSérie6
Flow
Too much for the machine
Simulation vs Experimental – reference cycle
Simulation is in agreement with experimental data
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Annealing effect (very slow cycles, Tshelf -25°C)
● Cycle #1: no annealing-
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0
20
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Tem
péra
ture
(°C
)
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Temps (h)
0.2
0.1
Pre
ssio
n (m
bar)
Cycle #1Température (°C): Pression (mbar):
Produit - milieu MKSProduit - arrière PiraniProduit - façadeConsigne étagère
-40
-20
0
20
40
Tem
péra
ture
(°C
)
403020100Temps (h)
0.2
0.1
Pres
sion
(mba
r)
Cycle #2Température (°C): Pression (mbar):
Consigne étagère MKSProduit - milieu PiraniProduit - arrièreProduit - façade
Inte
nsité
(u.a
.)
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Lyophilisat Cycle #1
Inte
nsité
(u.a
.)
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Lyophilisat Cycle #2
Cycle #2: annealing-10°C 1 h
Amorphous XRPD
Compliant aspect
Crystalline XRPD
Compliant aspect
Real freeze drying conditions confirm the impact of a -10°C annealing on the cake cristallinity
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Simulation vs experience: product B
00.050.10.150.20.250.30.35
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0.0010.00
0 10 20 30
Subl
imat
ion
flow
(g/h
-via
l)
Tem
pera
ture
(°C
)
Time (h)
simulation/experience - Cycle # 6 product B
simul bottom Tsimul ice front Tshelf TExperimental product T
Kv =11 W/m²°C
P= 100 µb
A very high value of Rp is observed – This is consistent with the continuous heating of the vials, The shape of the Rp (height) curve does not fit with the usual convex scheme (“Pikal” model)
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Industrial trial 1- Pharmaceutical Elegance issueFor first industrial trial it was decided not to anneal :
Surprising defects were observed. 3 zones cakes : central zone was slightly collapsed but : no melting, no bubble like defect- No puffing
Explanation : the upper part is amorphous, due to absence of annealing and not collapsed because of the low initial temperature- the medium part is amorphous too but collapsed due to T>Tcollapse. Eventually the bottom part is exposed to high temperature (-10°C ) and can recrystallize (in situ annealing)
To anneal …. That is the answer !
crystalline
amorphouscollapsed
No collapseT < -25°C
Collapse-25°C < T < -10°C
CrystallineT > -10°C
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Flac
on #
1Fl
acon
#2
Flac
on #
3
Dessus du flacon Fond du flacon
Vial
#1
Via
l #2
Via
l #3
TopBottom
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Proposal to speed up the sublimation step
Inverted profile : plateau at +10° C the decrease @ 5 may allow to win 2 hours sublimation (simulation 29.5 h)
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0,0
10,0
20,0
0 10 20 30 40
Temps (h)
Tem
péra
ture
(°C
)
0
0,05
0,1
0,15
0,2
0,25
Flux
éva
pora
toire
g/h
.flsimul bottom T
simul ice front T
Etagère
Flux théorique nouveau cycle
Max flow ~10.1 kg/h
The most dangerous zone is the end of the primary sublimation : indeed due to the high Rp value, the ice front is hot, the shelf temperature should be moderated,Vice versa at the beginning, the ice front is at lower temperature : it makes sense to accelerate the sublimation rate at the beginning and to slow it at the end !
Mean flow: ~7,5kg/hMax flow : ~10 kg/h
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Industrial Cycle 2 – simulation vs . realityEssai 2- sonde centrale
simul vs exp
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0,0
10,0
20,0
0 5 10 15 20 25 30 35
Time (h)
Tem
pera
ture
(°C
)
0
0,05
0,1
0,15
0,2
0,25
Evap
orat
ive
capa
city
g/h
.flsimulation bottom T simulation front T shelf
Experimental sonde centrale theoritical evaporative flow
The simulation is very close to the experimental results ( with a probe positioned far from the border)
center
Water content : 0,1% in all tested vials
Annealing crystalline cake
10.000 vials inspected : No defects
About 15 % increase in Yield and 15 % decrease in the industrial cost of goods
7000
6000
5000
4000
3000
2000
1000
a.u.
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vial #1- top vial #1- bottom vial #2- top vial #3- top
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Product B final proposal for validationIndustrial trials shelf T profile
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0
20
40
60
0 10 20 30 40 50
time (h)
T°C
Trial 2Profile for validation
Longer freezing step
Annealing
For elegance
Longer plateau at 10°C to speed-up
Shorter by 1 hour to be sure to keep operation below 48 hours
Three successful validation batches , then routine production
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CONCLUSION● Application of the methodology :
● Basic physical chemistry information (Tg’, eutectic temperature …)
● Going forth and back from simulation to experiment and experiment interpretation through theoretical parameters (Kv, Rp(h)) provides insight in the physics of the sublimation and allows to understand and predict
● Straightforward approach : elegance & industrial issues solved
● Concrete benefit:● Validation batches with full rational
● Compliant product
● Optimized productivity
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Acknowledgements ● Thanks to all the team members that contributed to make
this deliverable happened :
● Marie Wacquet● Cecile Allais● Lionel Bardet● Estelle Brun● J.R.Authelin● Stephane Devaux● Christian Hermandesse● Tim McCoy ● Charlene Moitie
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Thank You
Do you have questions ?