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Continued Process Verification of a Lyoproduct

Authors:

Abstract

Critical Quality Attributes are linked to the critical formulation temperature and critical product parameters. Process robustness testing during development is explained and the implementation into the regulatory documents as well as an overview on cpv of the product analysing the lyocycle as well as the critical quality attribute residual moisture is shown.
13.02.2020
1
explicat –
matching your development requirements
Freeze-Drying Technology Summit
Vienna 13.-14.2.2020
Dr. Andrea Weiland
Explicat Pharma GmbH
Georg-Knorr-Strasse 4
DE-85662 Hohenbrunn
contact@explicat.com
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Lyocycles process verification - Overview
Connued Process Vericaon of a Lyocycle
Background of the Product – Predominantly Crystalline Matrix
Specicaon/Crical Quality A#ributes
PPQ-Evolvement of the Lyocycle
The Regulatory Lyocycle
The CPV Program
Current Results
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Lyocycle process verification – Critical
Quality Attributes of a Lyo Product
Analysis of critical quality attributes
(CQA's) of a lyo product
Appearance (of Lyo cake)
Reconstitution Time
Clarity/Colour of solution
Identity/Assay/Purity
Water content
Sterility
Endotoxins
Subvisible and visible particles
Container closure integrity (no leaks)
In blue – CQA driven by
Formulation and Lyo
process
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Lyocycles process verification – Critical
Formulation Temperature (CFT)
critical formulation
temperatures (CFT) in freeze
drying
Crystalline matrix* - Teut
Amorphous matrix* - Tg'/Tc
CFT depending on the
physical state drives the
design of the lyo cycle
*(predominantly)
XRPD
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Lyocyle process verification and Related
Critical Product Parameters
related critical
process
parameters
lyophilization
Critical Process Parameters
(CPsP):
Pressure (P) (Torr, Bar, Pa)
(relevant for chamber and
condenser)
Water vapor concentration
(molecules/m3) (linked to
pressure)
Gas flow velocity (u) (m/s)
(between chamber and
condenser)
Etc.
Critical Process
Parameters dependent
on lyophilizer
engineering, design
and performance
(important to know –
qualification!)
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Lyocyle process verification and Related
Critical Product Parameters
related critical
product parameters
lyophilization
Critical Product Parameters
(CPtP):
TP(b) (Product Temperature) (°C)
is crucial for process control
Product Resistance (Rp) (cm² x
Torr x h/g: area normalized product
resistance) (stopper resistance normally
negligible)
Desorption Rate (DR) (%/h)
Residual moisture (RM) (%)
Critical Product
Parameter - Tp
determines whether
product will comply to
critical quality
attributes (CQA`s)
Tp must comply to
the critical
formulation
temperature
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Lyocycle process verification_ Lyo cycle
robustness studies
Lyo cycle robustness studies
„Robustness: Ability of a process to tolerate variability
of materials and changes of the process and
equipment without negative impact on quality“
Design Space of the Lyocycle
Establish process boundaries
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Lyocycle process verification
Lyo cycle robustness studies
Importance of Product Temperature TP in Freeze
Drying
TPis a critical product parameter which determines
important product quality attributes such as physical appearance, residual
moisture, storage stability, reconstitution time, etc.
TPcannot be controlled directly, but is influenced by
shelf temperature, chamber pressure, product resistance and various other
factors such as super cooling, environment, etc.
TPmust not exceed the critical formulation collapse
temperature TC or eutectic temperature TE during primary drying to avoid
collapse and melt back
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Lyocycle process verification
Robustness Testings to find out critical process
parameters (boundaries) in relation to:
Commercial scale chosen vials
Need to apply trays
Prediction of lyocycle time
Final vial format: optimized 70h cycle used as
basis for cycle variations
Robustness runs #1 -#11 done with
different shelf temperature and load
conditions
Final lab lyo cycle established and recipe
for transfer to commercial scale proposed
and discussed
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Lyocyle process verification CQA
Appearance
Critical Quality Attribute Lyo:
Physical appearance
100% visual inspection: correct cake volume and appearance
Not acceptable cake: „meltback“, „collapse“, „shrinkage“
Other CQA`s: reconstitution time, physical and chemical
stability, Tg', Tg and residual moisture determination, etc.
Elegant and
acceptable not acceptable
meltback
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Lyocycle process verification-process
boundaries
Crystalline matrix allows drying > Tg' (Tg' approx. -45°C), TS
range in primary drying tested
Annealing step to be sufficiently long to obtain uniform
crystalline matrix isimportant
Vial size (diameter) 26.5 instead of 30 mm important:
adaptation of lyocycle (less “agressive”) needed: 30% defect of
26.5 mm in direct comparison to 30 mm vial
Significant impact of tray (need to increase of annealing time)
Led to final optimized lyo cycle in the lab as basis for direct
transfer to production scale (PPQ)
Robustness Testing – Process Boundaries
(Lyo-Design Space) - Results
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Lyocycle process verification – the Tool
Use of TEMPRIS® for Dev./Production scale
Components and Operation Principle
Passive, wireless, battery free
Quartz based sensor, operating on the principle of temperature dependent resonance: after
excitation by a modulated microwave signal (2.4 GHz) the sensor keeps on oscillating in a
temperature dependent frequency. Overlaying the sensor response with the carrier signal leads to a
frequency shift from which the product temperature TPb can be derived.
https://www.tempris.com/freeze-drying-lyophilization/products/#c61342c6ec168e219 - see video
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matching your development requirements
Lyocycle process verification – the Tool
Use of TEMPRIS® for Dev./Production scale
Components and Operation Principle
wireless
battery free
Passive sensor operation
– no heat impact
real-time temperature
measurement system
Characteristics
Sensors can be sterilized
Sensors can be placed
and positioned aseptically with
RABS/ ALUS/ Isolators
at „hot and cold“ (critical)
positions of the freeze-dryer Accuracy of the complete system
+/-0.7 °C to +/-0.3°C (-60 °C to 40°C)
see www.tempris.com
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matching your development requirements
Lyocycle process verification – the Tool
Use of TEMPRIS® for Dev./Production scale
Requirements of an ideal PAT tool for successful implementation
of Modern Process Validation and Continued Process
Verification
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matching your development requirements
Lyocycle process verification – PPQ
Process Performance Qualification-
crystalline matrix
Predominantly Crystalline
Matrix:
- Freezing Tp < Tg‘
- Annealing to crystallize bulking
agent/Ostwald ripening
- Tp max. -45°C at the beginning
of primary drying (due to Tg‘ of
the amorphous phase) then can
be run „agressive“ until Tp=Ts,
steady state primary drying Tp
around -25°C to -30°C (Ts set to
+15°C)
- secondary drying Ts 40°C
same pressure as during
primary drying
Sensor 2 is on shelf 1 in the relative cold
position (center position)
Sensor 13 is on shelf 5 in the relative
hot position (near door)
At timepoint 41:40
Sensor 13 -3.1°C
Sensor 2 -17.6°C
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Lyocycle process verification -Evolvement
of the Lyocycle
Example for Production
Scale Batches - TP of 16
sensors located at
different critical
positions in the lyo –
(„Hot –Cold - spots“);
sensors: shelves 1, 3, 5,
6, 9, 12, 15, 18 center
and front door position
or duct position (45.000
vials scale)
PV1 more
homogeneous Tp
Due to adaptations to
the freezing step
All CQA`s within
acceptance criteria, 0%
cake defect, residual
moisture map: very
uniform low residual
moisture results
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matching your development requirements
Lyocycle process verification- CQA
Residual Moisture
Design-Space translated into Production
Scale – Results using PAT Tool TEMPRIS®
PV2
30sqm
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Lyocycle process verification-CQA
Residual Moisture
Design-Space translated into Production
Scale – Results using PAT Tool TEMPRIS®
Statistical analysis shows increased
homogeneity; CQA Residual
moisture well in target range – shelf
1 (top) and the position sampled
nearest to the condenser (P2d) is the
position with the highest residual
moisture
KF residual moisture ≤ 1.0%
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explicat –
matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3 Lyocycle development
In 32P2 Pharmaceutical development – 32P22 Drug
Product:
Development of the Lyocycle based on the matrix and the
Critical Formulation Temperature
Tg', Teut Discussion and Laboratory Scale Lyocycle
Robustness Development to establish the boundaries
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matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3 Lyocycle development
In 32P23 Manufacturing Development:
Translation into commercial scale freeze-drying process
using PAT Tool TEMPRIS® to monitor Tp in critical
positions – further adaptations done to address full
scale/freeze dryer performance boundaries
Physicochemical analysis to demonstrate Critical Quality
Attributes are constantly met
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Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT Tool TEMPRIS® -
Process Validation according to FDA and EMA – modern „PPQ“
*EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1
FDA Guideline
Guidance for Industry – Process
Validation: General Principles
and Practices/January
2011/cGMP
1) Process Design
2) Process Qualification
3) Continued Process Verification
PPQ Process Performance
Qualification
EMA Guideline
Guideline on process validation
for finished products –
information and data to be
provided in regulatory
submissions/February 2014*
1) Process Validation
2) Scale-up
3) Post approval change control
Continous process verification
and Annex 15 to EU GMP Guideline
„Qualification and Validation“
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matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3: Process Validation Lyocycle: in Module 32P35
Process Validation executed as “hybrid” - e.g. compounding
-”traditional” - Lyocycle modern
General Lyocycle Approach controlled by real time feed back
system TEMPRIS®:
Tp („hot/ cold“ spot)- Control Temperatures to be used as online feedback
system to be programmed into SCADA
SCADA: Supervisory control and data acquisition for supervisory
management
PLC: Programmable Logic Controllers
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explicat –
matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3: Process Validation Lyocycle: in Module 32P35
Process Validation executed as “hybrid” - e.g. compounding
-”traditional” - Lyocycle modern
General Lyocycle Approach:
For approval in the following a general lyocycle is presented that can be
used in industrial scale lyophilizers with different construction/performances
in relation to design, lyochamber - condenser design, condenser type, water
capacity (how much water can be frozen on the condenser), connection
(duct) between chamber and condenser where the water vapour gas stream
will be directed, use of aluminum tray or automatic loading (vials directly
loaded on the shelf with direct heat transfer), use of controlled nucleation
technology if available at approx. -5°C to – 10°C etc.”
Intent: change of equipment – no regulatory variation (or change)
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explicat –
matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3 Process Validation Lyocycle: in Module 32P35
General Lyocycle Approach
A general lyocycle is presented driven by Tp and chamber
pressure control criteria
Some example text
“Key in Freezing step is to reach Temperatures < Tg' and achieve complete
freezing, nucleation and crystallization of the bulking excipient and Ostwald
ripening to obtain uniformly frozen vials amongst positions by annealing to
achieve homogeneity within batch over shelves and within batches; if no
controlled nucleation available - supercooling to be addressed, if controlled
nucleation moderate adaptation of the lyocycle possible”
The detailed lyocycle that was subject of process validation/PPQ including
the details of the industrial lyophilizer used is an exemplary cycle meeting
the criteria defined in the general lyocycle.
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matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Module 3 Process Validation Lyocycle: in Module 32P35
General Lyocycle Approach
A general lyocycle is presented driven by Tp and chamber
pressure control criteria
Other cycles using different industrial lyophilizers with their specific
performance if they confirm to the general lyocycle and its boundary
conditions are acceptable.
Also by applying the Tp control concept (a real PAT tool) alternative
loadings are possible as the general lyocycle is adaptable. This
might be needed for cases of technical defects occurring.
As long as the boundary conditions are kept, i.e. the Tp
characteristics, the product quality attributes will be similar.
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explicat –
matching your development requirements
Lyocycle process verification and the
regulatory implementation
Regulatory Implementation using Tp by PAT
Tool TEMPRIS®
Outcome of the Regulatory Procedure regarding the
Lyocyle
Tp (over time) as process control accepted
Partial loadings possible
Adaptations are possible without need of a change or
variation procedure
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Lyocycler process verification
Continued Process Verification
For the approved product now produced in routine for market supply:
The CPV Program was defined based on the Risk Analysis/Assessment of
the Product
Source Documents: Batch record/IPC`s and CoA´s
Process Parameters (CPP`s) and the resulting Critical Quality Attributes
(CQA`s) are checked
e.g. CPP: oxygen limit - CQA: Assay
The lyocycle as a CPP - CQA: residual moisture and cake appearance
Yield (after visual inspection) as proof of robust process
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Lyocycle process verification
Continued Lyocycle Process Verification
using Tp by PAT Tool TEMPRIS®
Tp as process control – interface to SCADA
Hot and cold positions defined over the shelves positioned into the
previously identified critical positions
Lyocycle is evaluated after each run
Data collected and meta analysis is done
Allows for scientific interpretation of data in case of deviations (e.g.
delays with loading, loss of power) on basis of the development data
(lyorobustness – lyo design space)
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Lyocycle process verification
Continued Lyocycle Process Verification
using Tp by PAT Tool TEMPRIS®
Selection of known hot and cold spot
Positions:
Hot spot sensor 2 - shelf 1- tray 2
Cold spot sensor 4 - shelf 1- tray 5
Hot spot sensor 6 - shelf 5 – tray 2
Cold spot sensor 11- shelf 5 - tray 5
Cold spot sensor 12 - shelf 9 - tray 5
Hot spot sensor 13 – shelf 12 – tray 2
Cold spot sensor 15 – shelf 15 – tray 5
Hot spot sensor 16 – shelf 18 – tray 2
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Lyocycle process verification
8 sensors
Hot and cold positions -
critical positions
confirmed
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explicat –
matching your development requirements
Lyocycle process verification
8 sensors
Hot and cold
positions - critical
positions confirmed
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explicat –
matching your development requirements
Lyocycle process verification
8 sensors
Hot and cold positions
- critical positions
confirmed
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Lyocycle process verification
Black: Ts at the entrance
Red: Programmed Ts
Blue: average T of condenser
Green: pressure of vaccuum
pump used
Purple: programmed vaccum
(pressure)
Light blue: Tp PT 100 average
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Lyocycle process verification
Blue 20sqm
Red 30sqm
Same
lyocycle
(PB1)
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matching your development requirements
Lyocycle process verification
Blue 20sqm
Red 30sqm
Same
lyocycle
(PB1)
Same
lyocycle
(PB16)
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Lyocycle process verification
Blue PB1 30
sqm
Red PB2
30sqm
Same lyocycle
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Lyocycle process verification
Blue PB1 30
sqm
Red PB2
30sqm
Same lyocycle
PB13 30sqm
Same lyocycle
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Lyocycle process verification
CQA Residual Moisture
With PPQ batches residual moisture (2015-2016): residual moisture map 0.3-0.5%
18 lyo`s routine production: Results: average residual moisture from 10 vials (3 beginning, 4 middle, 3
end of filling process);Values: 0.2-0.7%, all well ≤ 1,0%
Range confirmed
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Lyocyle process verification
Recent Experiences with Deviations
Existing Product with traditional lyocycle validation, deviation during
routine production:
Power failures- 1st alarm 1min, 2nd alarm 17mins (shutdown of main
electric switch)
Pressure
increased! (CFT?)
2nd alarm pressure
might have been up
9.9 mbar instead of
500 µbar!
?? what to do with
the batch?
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Lyocycle process verification
Thank You for Your Attention
Questions?
Dr. Andrea Weiland
Explicat Pharma GmbH
Georg-Knorr-Strasse 4
DE-85662 Hohenbrunn
contact@explicat.com
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