A Practical Guide to Pharma 4.0 Realization

// For a successful Pharma 4.0 digital transition

This guide will go through the basic philosophy of the Pharma 4.0 initiative, describe its elements and enablers, and break down all cornerstone aspects and benefits. And most importantly, we will show you – in clear and practical steps – how your company can securely implement a successful Pharma 4.0 digital transition.

What is Pharma 4.0
Data Integrity by Design

Why is this important?

Pharmaceutical Quality

Digitalization & ICH Guidelines

Holistic Control Strategy

In Pharma 4.0 Realization

What is Pharma 4.0?


Pharma 4.0

Operating Model

Digital Maturity

How can we assess it?

From Industry 4.0

To Pharma 4.0

// Definition

What is Pharma 4.0?

Since 2015, a special group of pharmaceutical process analysts and engineers has been operating inside the non-profit organization of the International Society for Pharmaceutical Engineering. It was named the ISPE Pharma 4.0™ Special Interest Group (SIG). Its goal is to provide a road map for new challenges of digitalization, Industry 4.0, and the smart factory.

It is important to understand from the outset that Pharma 4.0 is not a single product or a series of products.

It is an operating model that runs from research to product development and all the way to commercial manufacturing. This initiative’s ideas were formed from the Industry 4.0 technological advancements, where pharma-specific additions were made at the operational and regulatory level.

The Pharma 4.0 digitalization tools enable a fully connected network structure and the elimination of decision silos.

They facilitate direct communication between different organization levels and guarantee complete transparency throughout the product lifecycle management circle. Moreover, the connectivity between various information systems, devices, and machines allows for a paperless, data-driven approach, identifying and solving different manufacturing problems.

Big data analytics are used to organize the business in a much more efficient way.

Interdisciplinary collaboration is now crucial. All SOPs (Standard Operating Procedures) are closely monitored through high-level automation between integrated equipment and processes. This guarantees an enhanced PQS (Pharmaceutical Quality System) and confidence in fact-based decision-making.

// Operating Model

Pharma 4.0

One common misconception is that Pharma 4.0 is all about IT and the use of new digital technologies on the shop floor.

On the contrary, although based on Industry 4.0 digitalization tools, Pharma 4.0 is more about the automatic fulfillment of the International Council for Harmonisation guidelines (ICH8 to ICH12), with greater emphasis on ICH Q10 PQS.

At the core of the Pharma 4.0 operating model lay some basic principles, which are critical towards implementing a Holistic Control Strategy Lifecycle Management.

A key enabler is “Data Integrity by Design.” But it can only be realized if it is based on the other key enabler, the organization’s “Digital Maturity” within the Industry 4.0 architectural framework.

However, apart from reaching digital maturity and data integrity through infrastructure and process re-design, an organization needs to consider different elements, such as resources, information systems, organization, processes, and company culture.

// how can we assess it?

Digital Maturity

The Pharma 4.0 operating model is based on matching the industry 4.0 model with the FDA Digital Maturity Model.

Nevertheless, the biggest hurdle that most of the pharmaceutical companies face before realizing the Pharma 4.0 initiative is the digital maturity level of their organization.

As we can see in the industrial evolution diagram on the left, different technological advancements led to different corresponding revolutionary changes in the industrial world.

By projecting this categorization on today's pharma manufacturing world, one will find out that most of the companies' infrastructure is at an Industry 3.0 level.

In contrast, others have entire production lines running on Industry 2.0 equipment and processes (i.e., using manually produced, paper-based manufacturing records).

Another way of assessing the digital maturity of a manufacturing organization is by acknowledging which of the below structural areas are present:

Unless such an audit of structural areas takes place, it is impossible to design a realistic and effective strategy for achieving a successful Pharma 4.0 deployment.

From Industry 4.0 to Pharma 4.0

As previously mentioned, Pharma 4.0 is based on Industry 4.0 digital systems and communications.
All the Regulatory requirements must be added, and the process performance systems are transformed into product quality monitoring systems.
The cloud-based IIoT (Industrial Internet of Things) technologies simultaneously control multiple processes and production plants while collecting more data.
The complete manufacturing environment can be monitored in real-time, configured automatically, and self-corrected through self-learning processes.
For example, by assuming high-level Pharma 4.0 readiness,
once a packaging line is plugged into a line management system, it should be automatically qualified, validated, and ready to use in a GMP (Good Manufacturing Practices) environment.
// Pharma 4.0 shop floor

An IIoT adaptive environment that monitors itself and controls itself.

// why is this important?

Data Integrity by Design

One of the main concerns of a drug manufacturing plant is the warranty of data integrity and high-level production quality.

Failing to do so will lead to a breach of contractual obligations, legal complications, order delays, and an increase in manufacturing costs.

Therefore, data integrity has to be the cornerstone of the Pharma 4.0 systems design.

Data is tracked throughout the manufacturing process and is available to ensure high-quality standards.

All business processes should:
Data is in the center of a Pharma 4.0 operating model.
It is continuously collected to provide real-time information that builds deep knowledge around the manufacturing process. It enables the implementation of a predictive control strategy.
So, it is evident that a Pharma 4.0 manufacturing strategy should include the following elements and enablers:
PQS elements:
// Using Digitalization and ICH Guidelines

Achieve Pharmaceutical Quality Excellence

Up until now, the pharmaceutical world has been facing a series of quality issues:
The market was flooded with low-quality drugs, as there was no secure way of observing and rewarding quality.

Competition on quality transformed into competition on price.

Increased drug shortages, with quality issues accounting for around 65% of shortages.

Moreover, in September 2017, the FDA released new guidance on advancing emerging technologies and their application to achieve pharmaceutical innovation and modernization.
The Pharma 4.0 operating model combined these areas of concern by merging the Industry 4.0 digitalization with the quality management process.
This is stated by the International Council for Harmonisation, mainly in the ICH Q10 guideline, concerning PQS.
For example, by assuming high-level Pharma 4.0 readiness,
once a packaging line is plugged into a line management system, it should be automatically qualified, validated, and ready to use in a GMP (Good Manufacturing Practices) environment.

Regulation for Pharma Quality leads to Quality by Design

However, we should note that a series of other ICH guidelines are also implemented by the Pharma 4.0 initiative:
Below is an official diagram of the ICH Q10 Pharmaceutical Quality System model.
One can observe the connections between the drug commercial manufacturing lifecycle and the previously mentioned PQS elements and enablers.
// why is it essential in Pharma 4.0 Realization?

What is the Holistic Control Strategy

For many years, pharmaceutical companies' research and production information have been isolated in "digital islands".
There was no overarching concept behind the system’s design. Data use for process optimization was limited to a local level. Finding solutions to manufacturing problems was time-consuming and inefficient. One had to navigate into different systems and manually connect relevant information. Nevertheless, without recorded, detailed, and automatically integrated knowledge of the control strategy processes, and organization of the data flow and data lifecycle cannot be made. The “data by design” principle cannot be implemented.

Shop floor Process => Cloud manufacturing App => Real-time production data => Process Optimization

It was decided that an end-to-end “Holistic Control Strategy” should be in place to realize the Pharma 4.0 initiative and achieve Pharmaceutical Quality Systems (PQS / ICH) Digitalization.

Holistic Control Strategy
A planned set of controls derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Such a strategy follows a product from Research through Development, Tech Transfer, and Commercial manufacturing. It enables control and holistic lifecycle management, providing synergy between digital automation and guidelines. It enhances the quality manufacturing focus, where QTTPs (Quality Target Product Profiles) are required for all products. Now, the information from machines and components is readily available without navigating different systems or searching into piles of paper-based records. The operators' comments can be automatically logged, making the continuous improvement process easy to implement

Holistic Production Control: From ICH Q10 to Pharma 4.0

This end-to-end manufacturing control strategy plays a crucial role in ensuring that the CQAs (Critical Quality Attributes) are met and QTTPs realized.

It ensures plug-in compatibility is achieved, and paperless data integrity is guaranteed.

A more simplified methodology to implement a Holistic Control strategy would have the following steps:

And since data integrity and automatic validation are at the core of Pharma 4.0, below is a complete diagram depicting all the various data and process flows needed.

Figure 5: Three-stage Pharma 4.0 process validation

Source: ISPE Biotech Special Interest Group

// Summarizing

The Benefits of Pharma 4.0

From the above discussion, it should be clear that Pharma 4.0 is a strategic choice for leveraging emerging digital technologies.

The gains from the shift in mentality and the requested investments can be summarized in the following points:

Holistic Control Strategy:
Manufacturing Optimization:
Complexity management:
Workforce benefits:
Given all these multi-level benefits, the shift to a Pharma 4.0 operating model should be a straightforward decision for a life sciences company.

However, many things need to change (from people’s mentality to infrastructure and processes) to reach the highest manufacturing performance levels and quality. In the following paragraphs, we will explain and give you examples of how you can safely make this transition.