> Pharma 4.

0
Your Roadmap to Digital
Manufacturing in Regulated
Industries
 Table of Contents

Introduction ……………………………………………………………………………... 3

What is Pharma 4.0? ………………………………………………………………… 5

Steps to Pharma 4.0 ………………………………………………………………….. 8

Industry 4.0 Fundamentals ……………………………………………………….. 12

Finding localized, scalable problems ……………………………………….. 17

Use Cases ……………………………………………………………………………………. 20

Case Studies ………………………………………………………………………………. 28

Conclusions ………………………………………………………………………………... 33
 INTRODUCTION:
TOWARDS DIGITAL MANUFACTURING FOR HIGHLY REGULATED INDUSTRIES

harmaceutical and biotech manufacturers face a number of unique challenges in

P the digital era. While new technologies have multiplied opportunities for process
improvements, regulatory oversight has slowed adoption relative to other industries.
Stringent requirements for documentation, data integrity, and process validation all
create an environment where compliance can outweigh continuous improvement.

Nevertheless, manufacturers who act smartly and decisively can benefit. There are more
tools for improving quality and efficiency than ever before. Many even promise to make
compliance an automatic, seamless part of the quality process.

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This guide provides a comprehensive overview of digital manufacturing for the
pharmaceutical industry.

Throughout, we’ll review use-cases, technologies, and strategies for applying digital
technology that you can use in your operations.

This is your roadmap for building digital capabilities in highly regulated industries.

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 CHAPTER 1

What is Pharma 4.0?

Defining Pharma 4.0

Pharma 4.0 is a framework for adapting digital strategies to the

unique contexts of pharmaceutical manufacturing.

In practical terms, it means more connectivity, more productivity,

simplified compliance, and the marshaling of production
information to respond to problems as they emerge.

The term was coined by the International Society for

Pharmaceutical Engineers to envision a digitally mature
pharmaceutical industry.

ISPE’s digital maturity model for Pharma 4.0.

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Defining Pharma 4.0
ISPE’s plan is holistic, outlining priorities for business, IT, and
manufacturing throughout a drug product’s lifecycle.
Their conviction is that digitalization will help organizations
achieve “business goals by operating faster, reducing costs,
and being more competitive and agile”.
More than just an approach to digital technologies, Pharma 4.0
is also a means of transforming the manufacturing workforce.
From connecting workers, to more human-centric workflows,
to shifts in company culture, humans are at the core of Pharma
4.0.
“[To] Manufacture pharmaceutical products with
maximum product and process understanding, data
integrity by design, efficiency and optimal resource
allocation on the basis of full digital data
transparency--to the benefit of the patient.”
-ISPE Pharma 4.0 Mission Statement
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Many of the key points in the holistic model, however, are
directly applicable to manufacturing.
For example, the pharma-specific maturity model anticipates:
- The elimination of data silos with better
communication across the lifecycle of drugs
- A lower-touch relationship with regulatory bodies as
data collection and sharing improves
- The elimination of paper-based processes
- A shift to risk-based regulation
- Improved agility, connectivity, and productivity--even
in highly regulated facilities
Pharma 4.0 envisions a manufacturing paradigm that allows
manufacturers to change and iterate, that connects resources
and workers, and that ultimately produces more quality
product with better patient outcomes.
 CHAPTER 2

Steps to Pharma 4.0

Stages of Digital Maturity
Broadly speaking, there are six stages of digital maturity. With
the least mature being elementary computerization and the
most mature being self-regulating, intelligent facilities, these
stages outline a path that all manufacturers can follow.

1.) Computerization - The first stage of maturity is simply

to introduce digital technology to automate simple
manual processes. The goal is to find repetitive tasks
that would be better performed by computers and
create the basis for a digital infrastructure.
2.) Connectivity - Here, manufacturing expand IT
infrastructure and lay the foundation to integrate IT,
manufacturing, and business functions.
3.) Visibility - This is the area where many manufacturers
Stages of digital maturity for Pharma 4.0. Manufacturers can unlock order-of-magnitude
will start to see substantial improvements. Connected gains in productivity by increasing connectivity and visibility without sacrificing compliance.
people, machines, and processes create a substantial
digital record of production that can be used to make
real-time, data-driven decisions.

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Stages of Digital Maturity Cont.

4.) Transparency - With more data, new insights about
complex systems become available. Advanced
analytics find opportunities for improvement that
were previously invisible.
5.) Predictability - Detail production records enable
manufacturers to correct problems before they
happen.
6.) Adaptability - This is the final stage of maturity. Here,
systems anticipate problems and initiate the proper
action by themselves. At their most advanced, these
are autonomous self-correcting systems.
We’re far from a reality in which pharmaceutical manufacturing
lines detect problems and self correct.
Still, this trajectory from a baseline of digitization and connectivity
to sophisticated, predictive systems is one that manufacturers can
take steps to achieve now. Indeed, with the right strategy, that
future might not be so far away.
Pharmaceutical manufacturers can realize significant gains by
finding small opportunities for digitization and beginning there.

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Bringing Industry 4.0 to Pharma

Outlining a strategy for digital transformation isn’t a trivial task. Nor is finding small, scalable
opportunities for improvement.

Now, with a destination in mind, the question becomes: How do we get there?

The answer is adopting an agile approach, privileging a steady evolution rather than a rapid revolution.

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 CHAPTER 3

Industry 4.0 Fundamentals

Industry 4.0 Fundamentals

While Industry 4.0 is often defined as a suite of technologies Changes in Control Models with IoT
converging on the modern shop floor, there are a few concepts
that tie them all together.

The first is the Industrial Internet of Things. More than a

technology, IIoT refers to the networking of disparate items,
sensors, and people across a manufacturing facility. This
connectivity creates a more holistic picture of manufacturing
processes, and helps to eliminate silos.

The other is cyber-physical systems (CPS). CPS are networks

that combine human and machine inputs to create better
communication and support between the different actors in a
factory. In simpler terms, CPS are connected systems that help
IoT moves from centralized, hierarchical control models to distributed, emergent models.
support humans on the shop floor by contextualizing their
activity across the digital and physical domains of
manufacturing.

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Cyber Physical Systems

What they are is less important than what

they do.

CPS help people make better decisions, find

new opportunities for improvement,
optimize the allocation of resources, and
improve quality by creating more responsive
working systems. With, CPS, humans work
hand-in-hand with digital manufacturing
systems.

Cyber physical systems (CPS) usher in a new era of efficiency by integrating humans within
the manufacturing environment.

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Emergent Control

Together, IIoT and CPS enable a bottom-up approach to

pharmaceutical manufacturing. Hierarchical control models
require more information before implementing changes. With
IIoT and CPS, control is emergent.

By emergent, we mean new patterns emerge as digital

systems operation. Specifically, the increased quantity and
quality of information enables manufacturers to identify local
problems in real-time, and to adapt their improvements
accordingly.

Accepting emergence means accepting that we can’t have all

of the answers prior to letting the system run and sampling its
output. Working with emergence is key to creating value How are Industry 4.0 and Pharma 4.0 different? Here’s a breakdown of the key similarities
through evolution, not revolution. and differences.

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Data Integrity by Design

Data integrity is one of the areas where Pharma 4.0 can With Pharma 4.0 solutions they are caught in real time. This
contribute the most. Indeed, the ISPE outlines “Data Integrity makes it possible to manufacture with a Right the First Time
by Design” as a desired outcome of digital maturity. approach and saves time in exception handling.

Nevertheless, documentation in the pharmaceutical industry is

often paper-based and error prone. Lack of standardization
leads to data loss between research, validation, and production
stages, and masks areas for process improvement. During
manufacturing, engineers record machine states, batch
information, and production schedules in paper forms. These
logs are prone to transcription error, are labor intensive to
keep, and difficult to reference. Often, mistakes are caught too
late, at the end of a process.

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 CHAPTER 4

Finding localized, scalable problems

Finding localized, scalable problems

The trick to implementing these concepts in practice is

learning how to see pharmaceutical manufacturing problems
from a different perspective.

Traditionally, changes have been large, and solutions

comprehensive. This required marshalling a significant amount
of organizational resources and energy around large,
multi-year projects.

With Pharma 4.0, improvement projects need not be massive,

costly endeavors.

It’s better to think in terms of localizable solutions that can be

implemented quickly and scaled as necessary.

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Many manufacturers, for example, might want to improve
quality, decrease process variability, improve data integrity,
and simplify complex processes like line clearance and
machine changeovers. Trying to solve each of these problems
with a single, top-down solution can lead to reduced efficacy
in each area.

Modern Pharma 4.0 solutions work within broader quality

management and manufacturing execution systems to give
manufacturers a faster, more flexible means of approaching
improvements. They can be configured and deployed quickly,
and iterated as processes and target improvements change.
What’s more, they automatically collect data while they run,
helping to provide the holistic physical/digital picture of
production necessary for the largest steps forward.

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 CHAPTER 5

Use Cases
Let’s look at some ways that manufacturers are already
creating value with Pharma 4.0 solutions.

Electronic Log Book

Electronic logbooks automatically document relevant

production information, streamlining a manual process while
dramatically improving data integrity. These logbooks can
compile and integrate information from machines and
operators, expanding process visibility. Further, electronic logs
can integrate photos, notes, reason codes, device history
records, and locations providing a more holistic record of
production than paper-based forms.
Electronic logbooks ensure that information is attributable,
legible, contemporaneous, original, and accurate (ALCOA).

Because these logs are digital, they can be easily accessed to

prove compliance.

Electronic logbooks make documentation and compliance reporting a seamless part of the
manufacturing process.

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Line Clearance
Many line clearance processes are complex, time-intensive
changeovers. With paper-based processes, workers may
spend a significant amount of time looking for the next step or
validating the execution of the previous one and less time
progressing through the procedure.

Interactive, digital line clearance applications can make line

clearance easier to navigate. Digital, IoT enabled work
instructions guide users through SOPs, increasing efficiency
ensuring that work is performed correctly and validated
automatically. The applications record how long each step of
the process takes, improving process visibility, and enabling
engineers to locate areas for process improvement. Because
these apps are collecting and communicating data in real time,
engineers can view process status as work unfolds, leading to
With Pharma 4.0, even complex procedures like line clearance can be made clear and simple.
reduced downtime and more effective scheduling.
Digital work instructions replace paper SOPs and ensure compliance.

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Electronic Batch Record

Batch record reviews require aggregating and reviewing a
substantial quantity of manufacturing data and process
documentation.
Much of the labor spent in the review process comes from
identifying incorrect or illegible entries, and correcting records
so that all production information is available for a given batch.
When it’s time for a batch record review, the
necessary information is accessible and easy to read.
Manufacturers can spend more time ensuring the
quality of a product and less time correcting
transcription errors. With more data available, it’s
easier to flag items to review by exception.

With Pharma 4.0 tools, manufacturers can make data

collection and validation a continuous, seamless part of the
manufacturing process. Information about manufacturing
processes is automatically collected as operators and
machines work, and all data is thereby attributable, legible,
contemporaneous, original and accurate.

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Process Visibility

In pharmaceutical manufacturing, the greatest barrier to

process improvement isn’t always regulatory constraints. In
many cases, it can be lack of process visibility.

With IoT devices and human-centric manufacturing

applications, manufacturers can break complex processes into
their constituent steps, creating a granular, picture of how
workers perform on the line. The applications let engineers
track individual operators performance at each step. This let’s
them create identify situations in which more training may be
necessary. It also helps engineers differentiate between poor
operator performance and poor process design.

In our experience, many of these changes are incremental, and

can yield significant gains in quality and efficiency without
triggering an audit or requiring revalidation.

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Clean Room Monitoring

IIoT makes it possible to respond to changes in environmental

conditions as they develop. Connected sensors can detect
when conditions may exceed established thresholds, and alert
operators to take the proper action before interrupting
production.

IoT technology makes Pharma 4.0 more transparent.

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Training for Regulated Environments

Many manufacturing processes require a significant
investment in training. Training can be slow, as manufacturers
have a difficult time replicating “real-life” production scenarios
in their training programs. This leads additional costs sunk in
training, and quality can suffer if operators aren’t trained
effectively.
Further, manufacturers can simulate processes in
production settings by running apps in an “offline” mode.
Here, training modules walk employees through a process
and collect data on their performance, while governed
execution mode makes sure that learners don’t impact
production.

Using manufacturing apps, manufacturers can design

Pharma-specific training applications to get employees on the
line fast. Engineers can break multi-stage processes into their
constituent parts with targeted modules, and embedded
media like videos and images help convey information to
different styles of learner. If it’s not possible to take workers off
the line during reskilling periods, training applications can be
configured to facilitate on the job training (OJT).

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Big Data Analytics

Manufacturers generate a truly massive quantity of data in the

course of operations. Yet most of this data isn’t used as the
basis for production insights. This is because it can be too
unwieldy or unstructured to be valuable (also referred to as
Data Rich, Information Poor, or “DRIP”).

One of the promises of Pharma 4.0 is the enhanced

interpretation of the data collected throughout a product’s
lifecycle. With advances in AI and machine learning, systems
are better able to parse and find connections within large data
sets.

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 Chapter 6

Case Studies
Case 1: Improving Process Visibility in an FDA Compliant Facility
THE CHALLENGE
This manufacturer faced a challenge shared by many
pharmaceutical manufacturers. Because their production took
place in segregated clean rooms, they were unable to
communicate effectively during production. Projects were
allocated to rooms, and the engineers used static, visual
markers, like colored magnets, to display room status.
This manufacturer had a difficult time tracking the progress of
jobs through rooms while still complying with FDA guidelines
for process documentation.
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THE SOLUTION
This manufacturer used a number of Pharma 4.0 tools to
address this issue.
Tulip offered a lightweight means of improving visibility within
a validated facility. Working with Tulip partners who
specialized in deploying technology in regulated environments,
this manufacturer digitized processes using a no code
manufacturing application platform. Instead of using magnets
to track room status, the manufacturer used no code
databases and visual dashboards to monitor and display the
status of each room in real time. IPads were placed outside of
each room, letting workers log room status, and creating a
digital record of production immediately available for analysis.
 THE SOLUTION Cont.
When room status changed, the manufacturing application
system immediately alerted the next team, reducing wasted
time between processes.

While this manufacturer scanned all necessary documents for

compliance purposes, the information wasn’t available to
inform process improvements. With the new system, the
information immediately helped to identify bottlenecks. Given
that this facility lacked the space for additional equipment,
optimizing production processes was essential for maximizing
value.

Custom manufacturing applications make it easy to improve control and visibility over sensitive In the end, this company was able to balance GMP compliance
tasks. and continuous improvement.

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Case 2: Digital SOPs Cleaning Complex Continuous Manufacturing Equipment
THE CHALLENGE
Another manufacturer used Pharma 4.0 techniques to improve
complex equipment setup. This included the disassembly,
cleaning, and assembly of individual parts of its manufacturing
line. This complex piece of continuous manufacturing
equipment consisted of 16000 individual parts, and each stage
of the manufacturing line took two weeks to clear. Instructions
for line clearance consisted of 30 SOPs packaged in an
80-page document, leading to slow execution times and
difficult validation procedures.
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THE SOLUTION
This company used digital application to guide operators
through the setup of the line. The application let workers route
directly to subtasks, eliminating the need to locate and
reference steps within the proper SOP. This made it easier for
new employees to learn the necessary steps needed to
disassemble, clean, and assemble individual parts of the
organization’s manufacturing line.
THE SOLUTION Cont.
These digital work instructions eliminated paper from the line,
and helped to record execution and validation data in the
course of the cleaning process.

These tools reduced the process from 10 to 2 day, and

simplified reporting.

Apps provide an easy to learn interface and speed up production.

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 Chapter 7

Conclusions
 CONCLUSION:
INDUSTRY 4.0 UNLOCKS PHARMA 4.0

T he pharmaceutical manufacturing industry is evolving at a rapid speed.

While the FDA and manufacturers both envision a world in which compliance is a lower
touch, collaborative exercise, balancing continuous improvement with compliance will
remain essential for years to come.

The promise of Pharma 4.0 lies in its ability to unlock new potential for productivity and
quality while making compliance a seamless part of the manufacturing process.

Manufacturers who take the necessary steps to embrace a digital future now stand to
benefit from seamless compliance, but it need not stop there. By adopting a Pharma 4.0
strategy, manufacturers can increase connectivity, efficiency, and agility.

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Tulip, the Manufacturing App Platform, is empowering the world’s leading manufacturers
to improve the productivity of their teams, the quality of their output, and the efficiency of
their operations. Tulip is currently deployed in FDA validated production facilities, and has
experience helping pharmaceutical manufacturers improve efficiency and profitability
while simplifying compliance.

Get in touch for a free consultation with our industry experts, and learn more at
tulip.co.