clogged filter
Challenges in Sterile Manufacturing
catalent pharma solutions
more products. better treatments. ™ reliably supplied.
Discover more solutions with Catalent.
Development Engineer Joseph Wojcik
of Multiple Product Lines on a Single Process Configuration, Case Study figure 2. Case Study: Process Configuration
figure 3. Fishbone Diagram Method
Problem Statement During technical transfer of two concentrations (high and low) of a polymeric bulk sterilized Blow Fill Seal (BFS) sterile product a common process was desired. Sterility Assurance Validation was executed and the low concentration product was validated successfully. However, the high concentration product clogged the clarifying filter at ~60% of complete bulk utilization.
Inadequate Pressure
Operator Technique
CLOGGED FILTER
Re-agglomeration
Filter
Execute bench study, determine required homogenization time to eliminate filter clogging
figure 8. Bench EFA Model for Full Scale Batch
Chemical Interactions
B/F/S
Filter EFA
1800
1400
Materials Polymer Molecular Weight
Homogenization Pump
figure 4. Execute an experimental batch, sample during formulation additions, and compare filterability The filter is becoming clogged as the slope approaches zero.
400
350
APPROACH Determine & explore the probable cause of the filter clog (Fishbone) Test hypothesis Confirm critical quality
Final Product
Reduce polymer molecular weight feasibility
250
DOE - Determine if drug product can withstand Homogenization to reduce molecular weight
200
Early Stage of Process
150
Formulation Progression: Polymer, Excipients, API, Bulk Sterilization
100
50
0 0
5
10
15
20
25
30
1200
4X Minutes
1000 800 600
2X Minutes
400
X Minutes
200 0 0
20
40
1600 g x 438 (scaling factor) ~700kg clogged filter on production scale
300
Grams of Filtrate
Study Design
5X Minutes
1600
Polymer concentration
Develop process capable to filter and fill entire bulk formulation. Concurrently, do not change the process configuration in a way that would void the current Sterility Assurance Validation. • Cannot increase tank pressure due to equipment constraints. • Cannot increase effective filter surface area (EFA) of filter. • Cannot change filter membrane type.
Pre Homogenization
Insufficient Mixing
Alternatives were considered but deemed inappropriate: 1 - waste (dumping unused formulation) 2 - time delays (filter replacement, re-sterilization) 3 – new process (potential to require new sterility assurance validation)
Challenge
Post Homogenization
Determine the minimum flow required on a bench-scale filter 120 g / min (full scale) / 438 (scaling factor) = 274 mg / min = Critical disk filter flow rate to maintain BFS operations
Grams of Filtrate
Buffer Tank
Man Batch Record / Operator Disconnect
Process Leads to Contaminants
Process Vessel
figure 6. General Homogenization Theory
Population
INTRODUCTION
www.catalent.com
Design: • Homogenize • Pull aliquots every X minutes • Carry forward aliquots to “final product” • Analyze “final product” aliquots
60
80
Minutes
100
120
~ 274 mg/min Critical Flow Rate
Operational limit defined. Parameters for 500 kg Batch Determined at Bench and Confirmed at Full Scale
Minutes
figure 1. Aseptic Manufacture in Blow Fill Seal (BFS)
350 g x 438 (scaling factor) ~150kg clogged filter
Development and Testing methods
Re-agglomeration during formulation is not root cause, clogging caused at initial polymer addition.
Bench disk filter studies for speed and cost control Critical Quality Attribute tests to confirm changes • Viscosity analysis • Assay analysis
Identical filterability profiles between 1st attempt and scrutinized experimental batch.
figure 5. Fishbone Diagram Method
Process Leads to Contaminants Inadequate Pressure Insufficient Mixing
Homogenization Time
Assay
Viscosity
X Minutes
Within Specification
Within Specification
2X Minutes
Within Specification
Within Specification
4X Minutes
Within Specification
Within Specification
Man
5X Minutes
Batch Record / Operator Disconnect
Within Specification
Product CQAs unaffected by homogenization
Operator Technique
CLOGGED FILTER
Re-agglomeration
Within Specification
Bench test design Adjust for effective filter surface area (EFA) • Bench top: 47 mm disk filter EFA = 12.56 cm2 • Production: 10 inch production filter EFA = 5500 cm2 • 5500 cm2 / 12.56 cm2 = 438 = Scaling Factor
Chemical Interactions Filter EFA Polymer concentration
Materials
CONCLUSIONS
Demonstrated that the use of an in-line homogenizer to shear the polymer in the formulation while maintaining the critical quality attributes of the product was possible and eliminated clogging. Delivered a single process configuration that meets product attributes, reduces cost and decreases time between manufacturing of high and low concentrations - No equipment changeover between product concentrations - Only one sterility assurance validation program to be maintained on a biannual basis • Steam in Place (SIP) Validation • Media Fill Validation
©2014 Catalent Pharma Solutions. All rights reserved
catalent pharma solutions
more products. better treatments. ™ reliably supplied.
Discover more solutions with Catalent.
Development Engineer Joseph Wojcik
of Multiple Product Lines on a Single Process Configuration, Case Study figure 2. Case Study: Process Configuration
figure 3. Fishbone Diagram Method
Problem Statement During technical transfer of two concentrations (high and low) of a polymeric bulk sterilized Blow Fill Seal (BFS) sterile product a common process was desired. Sterility Assurance Validation was executed and the low concentration product was validated successfully. However, the high concentration product clogged the clarifying filter at ~60% of complete bulk utilization.
Inadequate Pressure
Operator Technique
CLOGGED FILTER
Re-agglomeration
Filter
Execute bench study, determine required homogenization time to eliminate filter clogging
figure 8. Bench EFA Model for Full Scale Batch
Chemical Interactions
B/F/S
Filter EFA
1800
1400
Materials Polymer Molecular Weight
Homogenization Pump
figure 4. Execute an experimental batch, sample during formulation additions, and compare filterability The filter is becoming clogged as the slope approaches zero.
400
350
APPROACH Determine & explore the probable cause of the filter clog (Fishbone) Test hypothesis Confirm critical quality
Final Product
Reduce polymer molecular weight feasibility
250
DOE - Determine if drug product can withstand Homogenization to reduce molecular weight
200
Early Stage of Process
150
Formulation Progression: Polymer, Excipients, API, Bulk Sterilization
100
50
0 0
5
10
15
20
25
30
1200
4X Minutes
1000 800 600
2X Minutes
400
X Minutes
200 0 0
20
40
1600 g x 438 (scaling factor) ~700kg clogged filter on production scale
300
Grams of Filtrate
Study Design
5X Minutes
1600
Polymer concentration
Develop process capable to filter and fill entire bulk formulation. Concurrently, do not change the process configuration in a way that would void the current Sterility Assurance Validation. • Cannot increase tank pressure due to equipment constraints. • Cannot increase effective filter surface area (EFA) of filter. • Cannot change filter membrane type.
Pre Homogenization
Insufficient Mixing
Alternatives were considered but deemed inappropriate: 1 - waste (dumping unused formulation) 2 - time delays (filter replacement, re-sterilization) 3 – new process (potential to require new sterility assurance validation)
Challenge
Post Homogenization
Determine the minimum flow required on a bench-scale filter 120 g / min (full scale) / 438 (scaling factor) = 274 mg / min = Critical disk filter flow rate to maintain BFS operations
Grams of Filtrate
Buffer Tank
Man Batch Record / Operator Disconnect
Process Leads to Contaminants
Process Vessel
figure 6. General Homogenization Theory
Population
INTRODUCTION
www.catalent.com
Design: • Homogenize • Pull aliquots every X minutes • Carry forward aliquots to “final product” • Analyze “final product” aliquots
60
80
Minutes
100
120
~ 274 mg/min Critical Flow Rate
Operational limit defined. Parameters for 500 kg Batch Determined at Bench and Confirmed at Full Scale
Minutes
figure 1. Aseptic Manufacture in Blow Fill Seal (BFS)
350 g x 438 (scaling factor) ~150kg clogged filter
Development and Testing methods
Re-agglomeration during formulation is not root cause, clogging caused at initial polymer addition.
Bench disk filter studies for speed and cost control Critical Quality Attribute tests to confirm changes • Viscosity analysis • Assay analysis
Identical filterability profiles between 1st attempt and scrutinized experimental batch.
figure 5. Fishbone Diagram Method
Process Leads to Contaminants Inadequate Pressure Insufficient Mixing
Homogenization Time
Assay
Viscosity
X Minutes
Within Specification
Within Specification
2X Minutes
Within Specification
Within Specification
4X Minutes
Within Specification
Within Specification
Man
5X Minutes
Batch Record / Operator Disconnect
Within Specification
Product CQAs unaffected by homogenization
Operator Technique
CLOGGED FILTER
Re-agglomeration
Within Specification
Bench test design Adjust for effective filter surface area (EFA) • Bench top: 47 mm disk filter EFA = 12.56 cm2 • Production: 10 inch production filter EFA = 5500 cm2 • 5500 cm2 / 12.56 cm2 = 438 = Scaling Factor
Chemical Interactions Filter EFA Polymer concentration
Materials
CONCLUSIONS
Demonstrated that the use of an in-line homogenizer to shear the polymer in the formulation while maintaining the critical quality attributes of the product was possible and eliminated clogging. Delivered a single process configuration that meets product attributes, reduces cost and decreases time between manufacturing of high and low concentrations - No equipment changeover between product concentrations - Only one sterility assurance validation program to be maintained on a biannual basis • Steam in Place (SIP) Validation • Media Fill Validation
©2014 Catalent Pharma Solutions. All rights reserved
