An Intro to Pharma 4.0: Implementing Industry 4.

0 in Highly Regulated Industries

Pharmaceutical and biotech manufacturers face a number of unique challenges in 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.

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.

Chapter One: What is 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.
The ISPE’s digital maturity model for Pharma 4.0

The 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

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 Two: Steps to Pharma 4.0

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 digital infrastructure.
2. Connectivity – Here, manufacturing expands IT infrastructure and lays the foundation to integrate IT,
manufacturing, and business functions.
3. Visibility – This is the area where many manufacturers will start to see substantial improvements. Connected
people, machines, and processes create a substantial digital record of production that can be used to make
real-time, data-driven decisions
4. Transparency – With more data, new insights about complex systems become available. Advanced analytics
find opportunities for improvements 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.
Stages of digital maturity for Pharma 4.0. Manufacturers can unlock order-of-magnitude gains in productivity by increasing connectivity and
visibility without sacrificing compliance.

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.
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.

Chapter Three: Industry 4.0 Fundamentals

While Industry 4.0 is often defined as a suite of technologies 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 support humans on the shop floor by contextualizing their activity across the
digital and physical domains of manufacturing.
IoT moves from centralized, hierarchical control models to distributed, emergent models.

What they are is less important than what they do.

CPS helps 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.

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.
How are Industry 4.0 and Pharma 4.0 different? Here’s a breakdown of the key similarities and differences.

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 through evolution, not revolution.
Data Integrity by Design
Data integrity is one of the areas where Pharma 4.0 can contribute the most. Indeed, the ISPE outlines “Data
Integrity by Design” as the desired outcome of digital maturity.

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.

With Pharma 4.0 solutions they are caught in real-time. This makes it possible to manufacture with a Right
the First Time approach and saves time in exception handling.

Chapter Four: 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 marshaling 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.

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.

Chapter Five: 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.

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 reduced downtime and more effective scheduling.
With Pharma 4.0, even complex procedures like line clearance can be made clear and simple. Digital work instructions replace paper SOPs and
ensure compliance.

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.
With electronic batch records, 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.

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.

Process Visibility
In pharmaceutical manufacturing, the greatest barrier to process improvement isn’t always regulatory
constraints. In many cases, it can be a 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 lets them 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.

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.

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 to additional costs sunk in training, and quality can suffer if operators aren’t trained effectively.
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 learners. 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).

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.

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.

Chapter Six: Case Studies

It helps to see how these individual use cases come together to create value on the shop floor. Let’s look at
a case study to see how one manufacturer used Pharma 4.0 tools and concepts to foster continuous
improvement in a highly regulated environment.

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.
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.
Custom manufacturing applications make it easy to improve control and visibility over sensitive tasks.

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.
In the end, this company was able to balance GMP compliance and continuous improvement.

Visibility is an integral part of Pharma 4.0.

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.
The Solution
This company used digital applications to guide operators through the setup of the line. The application lets
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.
Apps provide an easy to learn interface and speed up production.

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 days and simplified reporting.

Chapter Seven: Conclusions

The 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.
Improve quality and simplify