Enabling Broader Adoption ofProcess Intensification in Biopharma
July 9, 2021 | by Ganesh Kumar

The benefits of process intensification (PI) in biopharmaceutical manufacturing are well established: PI enables manufacturers
to increase volumetric productivity, reduce timelines, decrease facility footprint, lower costs, or improve flexibility. However,knowledge about PI implementation — from the costs to the technological and regulatory aspects, and risk mitigation — is lessubiquitous.
PI means different things to different organizations, depending on the manufacturer’s goals and the drug modality. One of
the most common misconceptions about PI is that implementation always applies to the entire manufacturing platform,
which would involve a semi-continuous flow from upstream to drug substance. But no set pathway exists.
As is commonly observed, a stepwise approach helps build confidence and familiarize the manufacturer with PI, allowing themto equip for a more platform-level intensification in the future. Numerous manufacturers around the globe are implementing
PI strategies based on data-supported business- and process-improvement decisions.
Successful intensification implementation has become routine, quashing another common PI misconception: the fear of beinga “test bed” versus being an early adopter. Manufacturers and many solution providers are gaining substantial experience innavigating implementation challenges, whether the manufacturer wants to adopt a stepwise approach or an end-to-end
implementation of PI. Guidance in selecting and developing the right intensification strategy, as well as implementation andregulatory process assistance, are no longer difficult to secure.

Decision-Making Tools Guide
Effective Process Intensification
Strategy Evaluation
Implementation cost versus return on investment (RoI)
represents another less-understood aspect of PI. In
determining both up-front costs and total cost ofownership, value chain services that comprise process
mapping, economic modeling, and conceptual design tools
can empower manufacturers to make a more informed
decision in selecting the right PI strategy for theirprocess(es).
“The key challenge is that there is no single massive stepchange that brings cost reduction if you are just looking at
the prices. You need to consider where you can get the best
benefit in terms of investment,” explains Andrew Sinclair,President and Founder at Biopharm Services, a pioneer indeveloping process and economic modeling tools for thebiopharma sector.
Manufacturers looking to evaluate process intensificationthat achieves productivity gains and cost savings in anexisting facility or process commonly adopt a highinoculum fed-batch process which involves operating theN-1 step in a perfusion mode and inoculating theproduction bioreactor at a higher viable cell density.
Using this strategy, manufacturers can increase productivity
up to 1.6 times and decrease the associated cost of goods(CoGs) by up to 50%.
Another current trend is manufacturers seeking long-term
perfusion approaches in upstream production bioreactors.
Over the next decade, a significant number of non-mAb
modalities — high potency, low-dosage products — areprimed to enter the market. These products generally
require low throughput (e.g., up to 300kg/year) to
manufacture, making perfusion approaches more attractive
as manufacturers can drastically reduce facility footprint,
capital expenditure (CAPEX), and operating expenses(OPEX) — allowing them to scale-out/up and enter newmarkets more swiftly.
For manufacturers seeking strategies applicable to highthroughput production of blockbuster therapies (typically>1000kg/year), adopting a concentrated fed-batch-based
intensified process enables them to switch from legacy
stainless steel (SS) manufacturing facilities to single-use(SU) facilities. With this approach, manufacturers cansignificantly lower their facility CAPEX and footprint in USP
compared to SS facilities, and achieve almost 3-4 times
the productivity compared to standard SU fed-batchapproaches.
10In any scenario, interaction with solution providers at an
early stage is paramount; it provides both the customer andthe solution provider data to determine if and where PI
implementation makes the most sense.

Proper Timing Eases Implementation
When intensification alters a process, it must be validated
again. Consequently, manufacturers should aim to
implement PI changes at a stage that minimizes regulatory
hurdles.

“Experts agree that manufacturers
considering process intensification for
new products should implement it as
early as possible in the molecule life
cycle — ideally during or before phase 1
clinical trials,”
Kurt Brorson, Ph.D.
VP, Technical at Parexel

A manufacturer in the discovery, toxicology, or even a
preclinical phase, is in the “sweet spot,” the ideal time toevaluate intensification, to compare results — in terms ofproduct attributes and quality — to a baseline reference,
whether it is batch data or the information comes fromanother process.
Early-stage intensification evaluation helps themanufacturer build a framework: an idea of the work
packages, deliverables, and the interactions they may needto have with regulators to implement such a change during
the preclinical or clinical phase (or even the commercialphase). As noted above, the earlier a manufacturer is inproduct and process development, the less impactful
hurdles like the required effort, costs, process validation,and timeline impact are likely to be.

High-Throughput Scaled-Down
Tools Drive Efficient Development
and Scale-Up
Process development inherently offers an opportunity tocharacterize and optimize a process. The following
elements enable manufacturers to efficiently develop andscale up an intensified process that would include a (hightiter) cell line, clone selection/optimization, media, andprocess characterization:
1. The manufacturer should leverage high-throughput
representative scaled-down tools that mimic the process
on a production scale as closely as possible.
2. The scaled-down tools should be intensification-ready.
If this is not the case, one must spend significant timeand cost in retrofitting or building custom equipment toaccommodate intensification approaches. For example,
performing scaled-down experiments with intensifiedready, multi-parallel bioreactor systems such as ambr®
perfusion can help to accelerate the manufacturer’s
decision-making process in choosing the rightPI strategy.
3. Integration of the high-throughput scaled-down tools
with in-line/at-line process analytical technologies (PAT)and multivariate data analysis (MVDA) tools for an
efficient Design of experiments (DoE).
With the elements outlined above, manufacturers can not
only select and develop the right PI strategy but alsosignificantly reduce costs, de-risk projects, improvesuccess rates, meet requirements for Quality by Design(QbD), and accelerate time to Investigational New Drug(IND) approval by ~2 months during the process.

Process Automation Enhances Control
Over Critical Process Parameters
Automation, meanwhile, can depend on the type ofmanufacturer. A large pharma company might have a
different set of automation requirements for its
manufacturing network in general — more advanced
concepts like virtual twins, electronic batch records, or
having a “facility of the future” — leading to different
intensification integration requirements. A small or
medium-sized company may still be getting used tosingle-use processes, which involve a lot of manualinteraction and are not conducive to a high level ofautomation.

Again, a stepwise approach that initially addresses specificpain points is the most logical, and intensification-readytools are vital. An intensified process requires adequate
process analytical technologies to measure the criticalprocess parameters (CPPs) — including, but not limited to,cell density, dissolved oxygen (dO₂), titer, etc. — in realtime, combined with process automation with integrated
data analytics-based approaches that can then enablereal-time prediction and control down to the individualunit operations.

Early Collaboration Drives Efficient
Implementation
PI is becoming increasingly well-understood, and its utility iscontinuously evolving to meet specific manufacturer needs,driving its popularity and opening new applications. Not allprocesses require end-to-end intensification that would
result in a semi-continuous process/continuous process.
Proper decision-making tools can aid manufacturers indetermining a viable intensification strategy — applied toeither existing or new processes/facilities — based on factors
including facility type, molecule, cost, flexibility, productivity,
timeline, and drug demand/output.
Total solution providers understand the challengesassociated with each manufacturer’s unique intensification
pathway, from PD to manufacturing, whether approachedstepwise or end-to-end. Through its experience and knowhow in implementation of PI gained by working withpioneering manufacturers, Sartorius offers solutions andservices that guide its partners in selecting andimplementing an optimal intensification strategy.
To learn more about how Sartorius can help in yourintensification journey, please visit:www.sartorius.com/en/applications/biopharmaceuticalmanufacturing/process-intensification.

11About Sartorius

About the Author

The Sartorius Group is a leading international partner of thebiopharmaceutical industry and the research sector. We help
biotech scientists and engineers across the entire globe todevelop and manufacture medications from the initial idea toproduction.
Ganesh Kumar, MS
is Sartorius’ Market Entry
Strategy Manager,Protein-Based Therapies.
As part of the Protein-Based Therapies team at Sartorius,
Ganesh collaborates with clients and business areas onprocess positioning, building the technical platform, andsolution packages for process intensification. He has overeight years’ experience in the biopharmaceutical industry,both as an end-user and a solution provider. He is based inGöttingen, Germany.

Additional ResourcesB enefits of Process Intensification: Key Considerations
and Expert InsightsP rocess Intensification: Understanding the Optimal Wayto Maximize Productivity
 dapting Bioprocessing to Meet the World’s
AChanging Demands

Ganesh started his career at Lonza, Singapore, where hewas actively involved in the tech transfer, validation, andlarge-scale commercial manufacturing of blockbustermAbs. Ganesh joined Sartorius in 2016 as a Process Engineer | Consultant and was one of the key contributors tothe development of the P4S® conceptual design platform.

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