Life Sciences and Operations Practices

Advanced tech elevates

process modeling in batch-
processing industries
In high-volume batch-processing industries, reliable models of
manufacturing processes can help companies cut production costs while
improving quality and performance.
This article is a collaborative effort by Álvaro Carpintero, Evgeniya Makarova, Miguel Ángel Morán, Matthias
Spiegl, and Vanya Telpis, representing views from McKinsey’s Life Sciences and Operations Practices.

© Just_Super/Getty Images

June 2022
 Pharmaceutical, consumer health, and consumer
packaged goods companies have worked for
decades to achieve an expert-level understanding
of their end-to-end manufacturing processes
using various modeling techniques. Traditionally,
process modeling has relied almost exclusively
on human experience and expertise. Now, with the
help of newer technologies such as machine
learning, predictive modeling, and faster data
processing, process manufacturers can
build more advanced models that go further to
optimize processes even before producing
a batch, forestalling problems likely to occur
during batch production.
Companies can leverage these models to improve
performance and quality—even beyond what
regulators may require—and save time and resources.
Leading companies that use this tech-enabled
approach to process modeling have seen a reduction
in deviations (for example, products outside
specifications) of more than 30 percent and have
cut the overall cost of quality by 10 to 15 percent.
In addition to these tangible benefits, advanced
process modeling deepens manufacturers’
understanding of their production processes. With
these insights, plant operators can adjust critical
process parameters (CPPs) such as temperature or
pH and improve decision making during production.
The more adept manufacturers are at
process modeling, the better able
they are to monitor and control the CPPs
that determine a product’s critical
quality attributes.
1
Guidance for industry: Q8(R2) pharmaceutical development, revision 2, US Food and Drug Administration, November 2009.
2 Advanced tech elevates process modeling in batch-processing industries
In addition, the quality and R&D functions can
upgrade product and process parameters during
the next R&D cycle.
This article describes advanced process modeling,
introduces three use cases for it, and offers
guidelines to boost the likelihood of success
with its use.
Upgrading business process modeling
Process modeling is a manufacturing discipline
for understanding the effects of process inputs (raw
materials) and CPPs on final products. The more
adept manufacturers are at process modeling, the
better able they are to monitor and control the
CPPs that determine a product’s critical quality
attributes (CQAs). CQAs are the physical, chemical,
biological, or microbiological properties or
characteristics that should be within an appropriate
limit, range, or distribution to ensure the desired
product quality.1 In the case of shampoo, for example,
pH balance is a CQA. In pharma, nearly all CQAs—
including, to name just two, concentrations of active
principles and excipients—are highly regulated.
Process modeling informs the controls strategy that
defines what, when, and where to test to ensure
that the process performs as it should and maintains
the quality of the product. Controls may include,
for example, testing the chemical composition of
a product, and the technical parameters at every
machine in the process.
An effective process to control strategy is particularly
important when the product being made does
not have a well-characterized chemical structure
or its quality attributes are difficult to measure
due to limitations in testing or detectability. This is
generally the case with, for example, biologics,
which are manufactured in a plant, animal cells, or
other living system. Because finished biologics
cannot usually be tested to confirm all their
components and characteristics, the companies
that produce them strive to maintain uniformity
in their manufacturing processes to ensure product
consistency, quality, and purity.
Companies rely heavily on statistical models—
mathematical expressions of the relationships
between process parameters and obtained results—
for process modeling. Traditionally, these models
were based on scientific-first principles (for example,
chemical and physical equations) and/or
experimentation and then refined through statistical
analysis of historical performance.
New types of models can go further to provide a
deeper understanding of the statistical relationships
between raw materials and CPPs, on the one
hand, and product CQAs on the other. They can
help to identify the truly important drivers of
the process while isolating any noise or disturbances.
They also reduce the need for experimentation
when setting up processes and decrease the number
of testing points.
Unlocking significant value using
new models
Newer, more advanced process models can be
used in three ways: on a one-off basis, for set-point
modifications, and for online or continuous
use (Exhibit 1).

Exhibit 1

Product mastery
Product mastery models
models drive
drive impact
impact through
through specific
specific use
usecases.
cases.
Capabilities required for use of advanced process models, level
High
Medium
Low
~70% of impact ~30% of impact
One-off changes Set-point optimization Continuous use
Model identifies significant process Model analyzes variability of Online model continuously
improvements and tests potential inputs from batch to batch for receives process inputs,
hardware and process adjustments recipe adjustment predicts outputs, and may
prescribe corrective actions

Analytics
Use becomes less prevalent as Ongoing use involves heavy Typically, already optimized
process matures data science and problem- levers are optimized more
solving, eg, on other products frequently

Information
technology/ None Can typically be done in Requires automated data flow
operational current setup and model run supported by
technology information- or operational-
technology workstream

Selected Adjustment of reactor filling level; Recurrent but infrequent Real-time optimal parameter
examples changing valve settings reruns of the models based on suggestion
offline data, eg, simple tank
Addition of buffer capacity farm planning Full closed-loop approach

One-off changes in the distributed Challenging deeply held

control system or control loop operating paradigms

Advanced tech elevates process modeling in batch-processing industries 3

 One-off use
One-off uses of advanced process models are well
suited to situations in which a significant process
improvement is required and the model can identify
it. The model can also simulate potential process
adjustments and identify those that will deliver the
desired result—an important benefit if costly
equipment or infrastructure modifications will be
needed. For example, a large continuous
manufacturing site wants to try increasing the set
temperature in its reactor to reduce impurities.
Rather than running a series of potentially time-
consuming and costly experiments on the line,
the change can be first executed within the model
to predict the outcome.
Set-point modification
Use of models for set-point modification tackles the
constant variability of inputs from batch to batch.
Among the many sources of variability are uneven
quality of raw materials, changing environmental
conditions, and differences in proficiency among
machine operators. Effectively responding to this
variability is critical to maintaining consistent results
and limiting deviations.
Prior to starting a commercial batch, the
manufacturer can run the model with a set of inputs,
including, for example, raw-material quality
characteristics, technical parameters of the process,
and room temperature (Exhibit 2). The model will
then suggest adjustments to CPPs that effectively
account for variability.
Consider a pharma manufacturer that makes tablets
and sources the validated active pharmaceutical
ingredient (API) from two different vendors.
Although both are within specifications, differences
between them—for example, in tablet breakage—
affect the final product. For each batch, the process
engineer would run the model using as inputs the
specific quality attributes of the API being used; the
model would then recommend the parameter
settings for an optimal batch (in the example, a
batch with no tablet breakage).
Set-point modeling also can be used for root-cause
analysis of problems, where it can shorten
investigation times and identify effective corrective
or preventive actions. During an investigation,
the model could quickly simulate possible scenarios,

Exhibit 2

Machine learningmodels
Machine learning models identify
identify the
the biggest
biggest variability driversininquality
variability drivers qualitytest
test
results,
results, and
and simulate
simulate effects
effectsofofadjustment.
adjustment.
An automated, real-time data pipeline feeds a quality-control (QC) model

QC dashboard, illustrative

Blending Compression Coating Packing QC lab

Drivers of variation

Compression machine speed Coating room air pressure Assay QC test result

Batch A B C Batch A B C Batch A B C

4 Advanced tech elevates process modeling in batch-processing industries

reducing the need to run physical experiments to
test various hypotheses. Additionally, the model
could be used to unearth relationships that lie at the
root of repeated problems and could provide
solutions that would otherwise be difficult to identify.
Online modeling
An online model continuously receives process
inputs and predicts outputs; thus, it can foresee a
problem and raise the alarm for operators before
the problem occurs. The more advanced of these
models not only can predict problems but also
can prescribe corrective actions. Online models
have been demonstrated to increase the frequency
with which the manufacturer can get a batch the
first time and reduce the number of deviations. For
example, in a biomanufacturing facility, the optimal
end point of a reaction—the point at which an
indicator shows that the proper amount of reactant
has been added to a solution—is difficult to
determine and varies from batch to batch. An online
model could continuously monitor the process
and predict the best moment to end it, alerting the
operator and improving the yield.
Having a better grasp of the process could also
ultimately lead to fewer quality tests—in-process
and in the lab. With the ability to accurately
predict a quality attribute, there is a case for only
needing to control the parameters that impact
it and not the quality attribute itself.
A clear application of this logic is used in “soft
sensors,” which do not directly measure a quality
attribute but instead use a model to calculate it
based on other measurable parameters (Exhibit 3).
This is particularly helpful in situations where
directly measuring isn’t feasible or the process must
be frequently interrupted for taking samples.

Exhibit 3

Soft
Soft sensors
sensorsenable
enablein-process
in-processoptimization,
optimization,increasing
increasingthroughput
throughputby
byup
up to
to 15 percent.
15 percent.
Adjustment of process conditions based on product predictions

Machine learning model

Active pharmaceutical indicator optimizer
Machine learning model predicts critical parame-
ters not measured throughout the process, using Interface for the end user to understand optimal
upstream data and early indicators parameters for ongoing batch production

Predicted Actual Batch 1 2 3 4

Reactor 1 2 3 4
100
Current fermentation time, hour 131 128 111 109
Predicted stop, hour 140 136 148 144

Offline samples, hour Model prediction, hour

96 136 140 144 148

Tier, kg 1,143 Tier, kg 2.120 2.175 2.248 2.394

Impurity 2, % 0.66 Impurity 2, % 0.85 1.18 1.38 1.92
0
Impurity 2
2

–100 0
July Oct Jan Apr July 100 120 140

Advanced tech elevates process modeling in batch-processing industries 5

 Prerequisites for advanced
process modeling
By paying careful attention to several dimensions
of advanced process modeling, manufacturers can
bolster their chances of success. Essential
dimensions to consider include an understanding of
the process, the availability of relevant data, and
a paradigm shift in ways of working.
Process understanding
Although models are intended to explain a process,
they are by no means substitutes for process
understanding. Knowledge acquired during R&D
and through process runs serve as the starting
point for model development.
Likewise, experts with deep process under­
standing are essential to confirm the results offered
by the model. During the model’s development,
process engineers can check to ensure all expected
relationships among parameters and attributes
have been identified. They also can validate other,
previously unknown relationships. Later,
during the continuous use of the model,
knowledgeable operators can accept or reject
prescriptive recommendations.
It is essential for organizations to build this process
understanding from development through
implementation. They can do so by involving site
process and quality engineers early in the
development of the model and then looping in
development engineers, who are in touch with
operations once the model is running.
Availability of data
Model development and testing require high-quality
data, particularly for machine learning models.
In addition to data about process parameters, the
model may incorporate data from numerous
other enterprise systems, including manufacturing
execution, supervisory control and data acquisition,
enterprise resource planning, laboratory information
management (LIMS), and information technology/
operational technology (IT/OT).
6 Advanced tech elevates process modeling in batch-processing industries
Preparing data for use in modeling can be extremely
time-consuming, particularly if data sources are
offline. Data will have to be stored in an accessible
location for use either in development or continuous
input. Additionally, data to train the model will
need to be structured and cleaned in advance. This
effort can take weeks to several months, depending
on the status of the data, and is usually completed
by a data engineer.
The types and update frequency of data will define
the needs for the IT/OT infrastructure that supports
the model. The ability to extract data automatically
from disparate sources will significantly reduce model
development time but can substantially increase
infrastructure costs; therefore, companies will need
to evaluate the trade-offs carefully. If a model is
to be used regularly, it must follow the product life
cycle, including updates, so source data must
be regularly updated as well.
Paradigm shift in ways of working
Building digital capabilities will be essential to
create and maintain advanced processing models.
Not only will the manufacturing need to have
modeling capabilities, but end users will have to be
trained on how models work, when to use them,
what limitations they have, and how to use them on a
day-to-day basis. Additionally, IT departments will
need to evolve into a true partner with a more active
role in process improvement.
Leaders will play a vital role by providing the
necessary opportunities for capability development,
enabling changes in ways of working, and
participating directly, including by strategically
deciding where process models are needed
and to what end. Rigorously tracking the impact of
modeling efforts will help them set priorities and
target investments.
The company, especially the quality organization,
will need to shift its mindset with respect to process
control. At a minimum, the objective of the control
strategy is to ensure predicted quality. Getting to this
 Web <2022>
<techModelling>
Exhibit 4
Exhibit <4> of <4>

The US FDA classifies process models based on impact, and applies different
The US FDA for
requirements classifies process models based on impact, and applies
each type.
different requirements for each type.
FDA requirements, by model type
Description Low-impact models Medium-impact models High-impact models

Typically used to Useful in assuring quality of Provide significant indicators

support product and product but are not sole indicators of quality of product (eg, a
process development of product quality (eg, most chemometric model for
(eg, formulation design-space models; many product assay; a surrogate
optimization) in-process controls) model for dissolution)

Requirements Discussion of how Model assumptions Data or prior knowledge

models were used to
make decisions during
process development
Tabular or graphical summary
of model inputs and outputs,
relevant model equations (eg, for
mechanistic models)
Statistical analysis, where
appropriate
Comparison of model prediction
with measured data
(with established first-prin-
ciples-driven models)—eg,
model assumptions, inputs
and outputs, appropriate-
ness of sample size, data
pretreatment
General discussion of
approaches for model
verification during
life cycle

Discussion of how other elements

in control strategy help to mitigate
uncertainty in model, if appropriate

point will necessitate changes to different quality
strategies such as the validation strategy and the
in-process control strategies. It is therefore
crucial that the quality organization play a major role
in developing process models, so it can adapt
accordingly and properly explain the new models
and related tools to regulators (Exhibit 4).
understanding to the next level. But it also requires
that companies build in-house expertise, finding the
right balance between off-the-shelf commercial
software and tailored solutions. Understanding the
technology is crucial for building trust in the model’s
recommendations, which in turn will increase the
users’ understanding of the manufacturing process.
Only then can manufacturers unlock the full potential
of advanced process modeling.

Using tech-enabled modeling in daily operations

can help reduce deviations, ensure consistent
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Álvaro Carpintero is a partner in McKinsey’s Madrid office, where Miguel Ángel Morán is a senior expert; Evgeniya Makarova
is a partner in the Chicago office; Matthias Spiegl is a partner in the Hamburg office; and Vanya Telpis is a director of
knowledge in the New Jersey office.

The authors wish to thank Helena Lubiano for her contributions to this article.

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Advanced tech elevates process modeling in batch-processing industries 7