process intensification and continuous bioprocessing by novasep · 2019. 7. 29. · white paper...
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Process intensification and continuous bioprocessing by Novasep
W H I T E P A P E R pharmaceuticalsbiopharmaceuticals
bio-industries
agrochemicals
functional ingredients
food ingredients
fine chemicals
biopharmaceuticals
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W H I T E P A P E R Process intensification and continuous bioprocessing by NovasepW H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep2
Introduction
Like petroleum, steel, automobile and consumer goods several decades
ago, the biopharmaceutical industry is currently considering a wider
implementation of continuous processing as part of a global process
intensification objective. Continuous processing is already well accepted on
the upstream processing side, since perfusion mode culture has been in use
for decades at an industrial scale.
Justifications for switching from batch to continuous chromatography
are numerous. Besides, the rising demand of biologics suggests reduced
processing and labor costs, footprint reduction, flexibility increase, more
stringent requirements for controlled, more consistent and improved quality;
and most importantly, the requirement for higher productivity and therefore
overall manufacturing cost reduction.
Last but not least regulators are pushing for continuous processing.
About Novasep
Novasep is a leading provider of purification technologies.
It has a unique business model based on 2 sets of offerings. “Process Solutions” with Process
engineering and supply of equipment, and “Manufacturing Solutions” with synthesis and
process development and contract manufacturing (CDMO).
Since decades Novasep designs, develops and operates continuous manufacturing processes.
This is perfectly illustrated by its production facility in Mourenx, France, where is produced
ultra-pure API omega-3 EPA: this is the largest FDA-inspected continuous HPLC Chromatography
Plant in Pharma, worldwide.
Thomas Flouquet, MSc, Application Specialist & Product Manager at Novasep
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 3
21 CFR 210.3 extracts:
Batch: a specific quantity of a drug or other material that is intended to have uniform character
and quality, within specified limits, and is produced according to a single manufacturing
order during the same cycle of manufacture.
Lot: a batch, or a specific identified portion of a batch, having uniform character and quality
within specified limits; or, in the case of a drug product produced by continuous process,
it is a specific identified amount produced in a unit of time or quantity in a manner that
assures its having uniform character and quality within specified limits.
Therefore definitions for both “batch” and “lot” are applicable to continuous processes.
FDA views “Though making the switch from batch to continuous manufacturing may be difficult, costly and time consuming, pharma manufacturers and CMOs should begin to consider the switch as in the long-run it will end up saving companies time, money and space”.
Dr. Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research. US Congress Hearing,
May 2015.
“Continuous manufacturing is consistent with FDA’s Quality by Design (QBD) efforts”.
FDA Perspective on Continuous Manufacturing. IFPAC Annual Meeting, Baltimore, January 2012.
Sharmista Chatterjee, Ph.D. CMC Lead for QbD ONDQA/CDER/FDA.
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W H I T E P A P E R Process intensification and continuous bioprocessing by NovasepW H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep4
Novasep developed the BioSC™ technology for industrial-scale purification of biologics.
BioSC™ is the first technology enabling different multi-columns processes as well as the integration of DSP steps. It allows:
Batch MultiColumn Chromatography (B-MCC)
Sequential MultiColumn Chromatography (S-MCC)
Isocratic MultiColumn Chromatography (I-MCC)
MultiStep MultiColumn Chromatography (MS-MCC)
In addition, single batch chromatography processes can be performed with BioSC™.
BioSC™: Bio System for Chromatography
BioSC™ Pilotexample of 2 MultiColumns set including pump module (left) and columns modules 1 & 2
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 5
BioSC™: Bio System for Chromatography B-MCC is the easiest multi-column process since it does not require any
adjustment of the batch recipe. It represents the simplest way to achieve
continuous loading (and if required, elution), by using several columns
operated in parallel that are never connected together.
Batch MultiColumn Chromatography (B-MCC)
Batch chromatography can be represented as a time sequence (chronogram),
presented in Figure 1.
In the following Figure 2 the chronogram of the batch process above will be
applied to a 4-column B-MCC process allowing continuous loading.
B-MCC aims at offering more flexibility. Indeed, BioSC™ Pilot can be configured for one batch module equipped with
one 5 cm ID column or for up to six modules equipped with six 20 cm ID columns. This represents a scale-up factor of
96.
A single system can bring an efficient answer to scale-up or multiproduct plants scenarios.
Consequently, B-MCC simplifies the process design by limiting the number of different systems and columns,
supporting standardization, reducing complexity and offering flexibility.
Another benefit is that B-MCC enables continuous loading and/or elution without any additional process development
nor validation. B-MCC can be easily integrated in any continuous process, encouraging streamlined manufacturing
(Table 1).
Figure 2
Representation of a complete B-MCC cycle (4-column recipe).
As soon as loading is over on column 1,
loading is performed on column 2
As soon as loading is over on column 2, loading is performed
on column 3
As soon as loading is over on column 3, loading is performed
on column 4
As soon as loading is over on column 4, loading is performed
on column 1
Table 1
Comparison between a standard batch chromatography skid and BioSC™ Pilot configurable from 1 to 6 columns
Figure 1
Example of time sequence for batch chromatography.
Load
Wash 1
Wash 2
Wash 3
Elution
Regeneration
Equilibration
Smallest column possible
Largest column possible
Scale-up factor
Possibility for continuous
loading/ elution
Standard batch chromatography skid on the market (4-180L/h)
5 cm ID 30 cm ID X36 No
BioSC™ Pilot from 1 to 6 column modules (5-100L/h)
5 cm ID 20 cm ID X96 Yes
Performance improvement
IN CONCLUSION: shorter process (streamlined),
higher flexibility and smaller equipment fleet.
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W H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep6
S-MCC process principles:In S-MCC the molecule of interest that breaks through the column is directly loaded onto
the next column that is connected in series. Therefore, loading can be significantly
increased on the first column without losing product.
As soon as the column reaches target saturation, starts the consecutive processing step
i.e. washing, then elution, regeneration, etc... while loading on the next column(s) is ongoing.
This process configuration can be defined as Period 1 (Figure 3).
After equilibration the column can be again loaded and enters Period 2 of the processing
sequence (Figure 4).
Figure 3: Period 1
Elution is performed on a saturated column. Loading is occurring on column 2, 3 and 4.
Figure 4: Period 2
Elution is performed on a saturated column. Loading is occurring on column 3, 4 and 1.
S-MCC is the most well-known example of multi-column process
based on “bind & elute” separation in biopharma. It is a very universal
purification process applicable to all chromatography media, process
solutions and molecules used in batch chromatography. The principle
of S-MCC came from a simple observation: batch chromatography for
both the volume loaded and the loading velocity.
Sequential MultiColumn Chromatography (S-MCC)
Elution Regeneration Equilibration Load
Elution Regeneration Equilibration Load
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 7
As soon as all columns of the S-MCC process have gone through the complete processing
sequence, one cycle is completed; a chronogram visualizes utilization of columns
throughout the processing time (Figure 5). S-MCC is based on countercurrent processing
flow of the stationary and liquid phases, and therefore allows for much more efficient
processing and for homogeneous exposure of the stationary phase to the loads compared
to batch, where most of the molecules are mainly exposed to the top section of the packed
column during loading, resulting in concentration gradients.
Figure 5
“Chronogram” (from BioSC™ Predict simulation software) of a complete S-MCC cycle (4-column recipe).
Process dimensioningFigures 6 and 7 help to quickly dimension the S-MCC process of an antibody
capture step based on the feed volume, titer and the processing time requirements.
They illustrate typical processing scenarios for a 4-column recipe depending on
the column ID.
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1
CON
FID
ENTI
AL N
OVA
SEP’
S PR
OPE
RTY
10 g/L
5 g/L
2 g/L
1 g/L
0,5 g/L
10 g/L5 g/L
2 g/L1 g/L0,5 g/L
10 g/L
5 g/L
2 g/L
1 g/L
0,5 g/L
200 L100 L
50 L
Figure 6
2
CON
FID
ENTI
AL N
OVA
SEP’
S PR
OPE
RTY
Figure 7
10 g/L
5 g/L
2 g/L
1 g/L
0,5 g/L
10 g/L5 g/L
2 g/L1 g/L0,5 g/L
10 g/L
5 g/L
2 g/L
1 g/L
0,5 g/L
2000 L1000 L
500 L
W H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep8
Figure 6
Processing time for a BioSC™ 4-column (5cm ID) recipe, depending on feed titer and volume to be processed.
For example, 4 columns of 5cm ID can process 100L of 2g/L harvest in 15h.
Or 4 columns of 5cm ID can process 200L of 10g/L harvest in 92h.
Figure 7
Processing time for a BioSC™ 4-column (20cm ID) recipe, depending on feed titer and volume to be processed.
For example, 4 columns of 20cm ID can process 1000L of 5g/L harvest in 17h max.
Or 4 columns of 20cm ID can process 2000L of 10g/L harvest in 57h max.
Volume of the bioreactor
Volume of the bioreactor
Feed titer
Feed titer
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 9
After the definition of the CQAs, different recipes (combination of process parameters)
pre-defined with the BioSC™ Predict process simulation software were tested and performance
results were compared to their reference batch process. An optimized S-MCC recipe was
performed on a 4-column BioSC™ Lab system with a load of a monoclonal antibody solution at
a concentration of 4.5 mg/mL. Same buffers and loads were applied for batch and S-MCC runs.
The following table 2 summarizes the main results of the study. BioSC™ run in S-MCC mode
exhibits important performance improvements compared to the batch process.
Product recovery is similar between Batch and S-MCC recipe.
Aggregates level is comparable.
Higher purity is reached with S-MCC recipe.
HCP (host cell protein) reduction rate is improved with S-MCC recipe.
Less protein A leaching was measured for S-MCC recipe.
DNA reduction rate is in the same range.
Productivity (expressed as mg of MAb/mL of resin/hour) gain is +200% for S-MCC.
Product loss in flowthrough is considered similar.
Columns positioned in series enable one to be loaded at a higher feed amount in a shorter time,
boosting performance of a single chromatography step. As an average, productivity increases by
200% (so X3), cost of goods (buffers and resins) are reduced by 3 to 4 times while CQAs remain in
the same range.
Critical Quality Attributes (CQAs) and process performance study
Sequential multicolumn chromaography (S-MCC)
Table 2
Results of a CQA and process performance study. S-MCC recipe set on BioSC™ Lab and comparison with batch.
Performance in the order of batch results (no color)
IN SUMMARY: shorter processing time, higher productivity
and smaller costs & volumes.
Recovery
(%) Aggregates
(%)Purity
(%)Reduction rate HCP
Protein A leaching (ppm)
DNA Log reduction
Productivity (mg/mL/h)
Loss flowthrough
(%)
Batch-MAb 4.5mg/mL
88 2.6 94 X47 1.6 2 14.6 0.3
BioSC-MAb 4.5mg/mL
89 2.9 98 X147 0 2 44.8 0.25
Performance improvement
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I-MCC aims at rehabilitating SEC at industrial scale. In I-MCC processes, as in S-MCC ones,
several short columns (e.g.: with 10cm bed height) are operated in a countercurrent mode
and therefore increase significantly process performance together with buffer reduction.
The following Figure 8 represents the concentration profile of two different populations
(blue and red) in a batch column during the separation (t1 and t2) and during elution (t3).
Red population includes species with a higher molecular weight than blue population and
therefore elutes earlier.
Size exclusion chromatography (SEC) is known to be a powerful separation technique
for analytical chromatography. But implementing SEC at industrial scale is a challenge.
It suffers from a lack of productivity and high buffer consumption. Besides this, it requires
long beds difficult to pack and manage at large scale.
Isocratic MultiColumn Chromatography (I-MCC)
Figure 8
Batch SEC chromatography separation principle.
t1 t2 t3Pure red population elution
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 1 1
In the following Figures 9 to 12 the sequences of a typical 2 populations separation
applying the I-MCC process are illustrated.
Figure 9: I-MCC Sequence 1
By positioning columns in series, no need to wait for complete separation.
Red collection starts as soon as red population elutes from column1.
Figure 10: I-MCC Sequence 2
Mixed zone (containing red and blue populations) is redirected on column2.
Fresh feed is loaded on column2 at the same time.
Figure 11: I-MCC Sequence 3
Pure blue population eluting from column1. Separation occurring on column2.
Figure 12: I-MCC Sequence 4
Period 2: Pure red population collection from column2.
On next sequence, mixed zone (containing red and blue populations) will be redirected on column1.
Fresh feed will be loaded on column 1. Then blue population eluting from column2.
Fresh feed
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W H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep1 2
In the following figure a chronogram represents utilization of columns throughout
the processing time of an I-MCC process (Figure 13).
Column 1 in series with column 2 Blue population collection from column 2
Column 2 in series with column 1 (Figure 11) Blue population collection from column 1
Column 1 alone (Figure 9)Red population collection from column 1
Column 2 alone (Figure 12)Red population collection from column 2
1
2
1
0
2
Fresh feed loading (Figure 10). Column 1 in series with column 2
Fresh feed loading. Column2 in series with column 1
I-MCC recipe was tested to purify a virus. Performance results were compared to their
reference batch process. The tests were performed on a BioSC™ Lab system with 2 columns
of 10 cm bed height. The same SEC media and buffer were used for batch and I-MCC test runs.
The following table 3 summarizes the main results of the study. BioSC™ run in I-MCC mode
exhibits much better performance than batch.
As for S-MCC, I-MCC enables one to load a higher amount of feed in less time, boosting the
performance of a SEC separation. As an average, productivity increases approximately by
5 to 6-fold while reducing buffer consumption by 85%. And last but not least, column size
can be reduced significantly, i.e. -96% SEC media. Only 2X10 cm (bed height) columns are
required compared to 1Xca.80 cm (bed height) column for a batch process.
Figure 13
Chronogram of a complete I-MCC cycle (2-column recipe).
Table 3
Results of process performance study. An optimized I-MCC recipe set on BioSC™ Lab and comparison with batch.
IN CONCLUSION: shorter processing time, higher productivity
and smaller costs & volumes.
Isocratic MultiColumn Chromatography (I-MCC)
Productivity improvement factor
Buffer consumption (20L virus solution
purified in 17h)
SEC media (20L virus solution
purified in 17h)
Batch Virus SEC 1 1700 L 200 L
I-MCC Virus SEC X5.5 256 L 8 L
Performance improvement
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 1 3
With one 3-module BioSC™ equipment, 3 chromatography
separations including a viral inactivation (VI) and in-line
dilution (ILD) can be operated simultaneously and continuously.
Straightforwardly, to switch from several batch skids to a single
DSP skid. Such a process has been made possible with BioSC™
technology in a cGMP environment (Picture 1).
Until now, one chromatography system was needed to execute one
chromatography step. Usually, standard processes involve three
chromatography columns, thus three systems.
MultiStep MultiColumn Chromatography (MS-MCC)
Picture 1
BioSC™ Pilot running in MS-MCC mode for the purification of a monoclonal antibody.
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W H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep1 4
The following illustration in Figure 14 shows how MS-MCC integrates chromatography steps
and how the upstream load can be treated in several cycles.
One single skid being able to perform the whole downstream process, from capture to
polishing, represents a drastic footprint reduction, and a serious cost reduction. One of
the key benefits is the elimination of non-added value steps (e.g. intermediate storage),
human intervention (safety, batch failure…) and equipment such as holding tanks.
Data for a 3-chromatography step process, comparing batch to MS-MCC process including
viral inactivation with BioSC™ are available (Table 4).
Productivity is increased by ca. X4 with MS-MCC.
Process time is reduced by 66% with MS-MCC.
Media consumption is reduced by 70% with MS-MCC.
Buffer consumption is reduced by 30% with MS-MCC.
Footprint is reduced by more than 50% with MS-MCC.
A closed DSP prevents human error and potential batch failure.
Figure 14
Representation of MS-MCC run, integrating 4 steps (3 chromatography steps + viral inactivation) of a MAb DSP.
ProtA = Protein A media; VI = viral inactivation, AEX = anion exchanger media
Isocratic MultiColumn Chromatography (I-MCC)
Table 4
Comparison between a standard batch process and a BioSC™ MS-MCC process.
Productivity (mg/mL/h)
Time reduction
(days)
Media consumption
(L)
Buffer consumption
(L)
Footprint reduction
Human error prevention
Standard batch process
2.7 3 20 100 - -
MS-MCC 10.5 1 6 70 >50% +++
All in all, shorter process (streamlined), higher productivity
and safety, and smaller costs and footprint.
Performance improvement
VI
Pro
A
AE
X
Mix
edm
ode
VI
Pro
A
AE
X
Mix
edm
ode
VI
Pro
A
AE
X
Mix
edm
ode
VI
VI
Cycle 1
Cycle 1
Cycle3 starts as soon as ProtA/Cycle2
is eluted
Cycle4 starts as soon as ProtA/Cycle3
is eluted
All 4 steps are run in parallel
Cycle2 starts as soon as ProtA/Cycle1
is eluted
Cycle 1
Cycle 1
Cycle 1
Time
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 1 5
BioSC™ Predict:
Models thermodynamics and kinetics of your chromatography batch process.
Suggests different MultiColumn Chromatography scenarios depending on your objectives.
Analyses performances of your optimized scenario.
Programs your BioSC™ unit.
Enables scale-up “prediction”.
Deeper process understanding is becoming more and more important to design a chromatographic separation that consistently delivers high quality products. With the process characterization method combined with the BioSC™ Predict software this can be achieved within a minimum of time. Furthermore, whatever BioSC™ technology is applied, process simulation is key for a successful, quick and simple implementation. Novasep designed its own simulation software, BioSC™ Predict, based on algorithms and real-case industrial data.
BioSC™ Predict Software
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W H I T E P A P E R Process intensification and continuous bioprocessing by NovasepW H I T E P A P E RProcess intensification and continuous bioprocessing by Novasep1 6
Conclusion
The rising demand of biologics combined with the need of deeper process
understanding, reduced development times and an ever-increasing
pressure on costs compels the Biotech industry to transform its production
models. Modernization of manufacturing tools includes the switch towards
continuous/intensified downstream processes assuring a maximum
of control by applying process and analytical tools.
BioSC™ Lab
BioSC™ Pilot
BioSC™ Predict
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W H I T E P A P E R Process intensification and continuous bioprocessing by Novasep 1 7
BioSC™ technology (B-MCC, S-MCC, I-MCC, MS-MCC and Predict software)
coupled with increased process understanding perfectly match all these objectives.
“The science exists to enable continuous manufacturing of pharmaceuticals. There are no regulatory hurdles for implementing continuous manufacturing. FDA supports the implementation of continuous manufacturing using a science and risk-based approach.”
Sharmista Chatterjee, Ph.D. IFPAC Annual Meeting (Baltimore, January 2012).
The objective is threefold:
> Shorter, streamlined processes.
> Higher productivity, flexibility and quality (through process understanding and control).
> Smaller costs, volumes and footprint.
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EUROPE Novasep ProcessSite Eiffel 81 boulevard de la Moselle - BP 50 54340 Pompey - FRANCEPhone: +33 383 49 70 00 Fax: +33 383 49 70 02
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INDIA Novasep IndiaFour Square Elegant, Block A, Flat 110 Madhavapuri Hills, Road5, Hyderabad - 500050 - INDIA Phone: +91 9866573377
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