Pharma 4.0: ISPE’s Vision for Operating Model


ISPE stands for International Society for Pharmaceutical Engineering, founded by a group of experts to discuss new challenges faced in pharmaceutical manufacturing. ISPE is a non-profit organization that provides technical and non-technical leadership for managing the life cycle of pharmaceutical products. In 2017, SIG (Special Information Group) was appointed to create a roadmap to facilitate “Industry 4.0” for pharmaceutical manufacturing. The prime objective of SIG was to reinvent Industry 4.0 for the adoption and leverage into the Pharmaceutical Industry. ISPE “Pharma 4.0” is based majorly on similar concepts and ideologies as that of Industry 4.0, it additionally has regulatory aspects based on  ICH guidelines, specifically ICH Q8 and Q10.

History of Industry X.0

Industry 1.0: The First Industrial Revolution, began in the 18th century with the utilization of machines to produce goods and the use of steam power, particularly in the weaving industry.  The mechanization of industries improved human productivity in many folds.

Industry 2.0: The Second Industrial Revolution started in the 19th Century, with the discovery of electricity. During these times, the concept of production and assembly line was introduced, by Henry Ford. The production line eased and increased the efficiency of manufacturing the automobiles, in turn reducing the production cost.

Industry 3.0: The Third Industrial Revolution started in the 20th Century, with the introduction of computers and their utilization to program the Industrial Process under human supervision.

Industry 4.0: The Fourth Industrial Revolution, which is currently ongoing. This revolution has enabled the complete automation of the industrial processes, by making the use of advanced computers and their integration into the network system, which allow internetworking communications of the production systems leading to the emergence of smart factories.

Smart Factories: The various components involved in the smart factories communicate with each other and mark the inception of total automation. These components are known as Cyber-Physical Systems that employ advanced control systems operated using softwares capable of internet connectivity {Internet of Things and Internet of Systems}, cloud computing and cognitive computing. The efficient communications and availability of information have enabled the digitization of manufacturing systems.

The Germans were the firsts to adopt the Fourth Industrial Revolution, named it I 4.0 when they initiated the projects that promoted the digitization of Manufacturing Systems.

Barriers of Industry 4.0 into Pharmaceutical Industry

It’s very right to say that the pharmaceutical manufacturing industry is not keeping up the pace with the advancing technologies. It is attributable to the stringent regulatory requirements that have slowed down the implementation process. For regulatory agencies, compliance with the existing standards matters more than the adoption of new technologies. It is believed that the pharmaceutical industry is highly regulated, and it can’t be left to machines. But the industry has started to realize the benefits of advanced technologies that can enhance productivity and improve quality at the same time. This hints at the inception of automation in achieving regulatory compliance in pharmaceutical manufacturing.

Evolution of Industry 4.0 to Pharma 4.0

  • Very often, Pharmaceutical organizations experience quality shortcomings that eventually lead to 483 observations and warning letters from regulatory agencies. Every year, approximately 4500 drugs are recalled alone in the USA. This recalling costs a great deal to the organizations.
  • Currently, the pharmaceutical industry is trying to adopt new strategies that can mitigate quality-related incidents. Lean Six Sigma tools are employed to improve product quality in pharmaceutical manufacturing.
  • In 2004, the US FDA published a guidance document entitled “Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practices Regulations” that insisted manufacturers implement modern quality systems and risk-based approaches to meet the expectations of the regulatory agencies.
  • In 2009, ICH Q8 guidelines were revised to incorporate the principles of “Quality by Design”(QbD); it stated that the quality cannot be just monitored but should be built into the product. Despite these measures, quality violations of pharmaceutical products continue to be unabated.
  • The best solution to these problems is the digitalization of platforms. What is required is, the model for the implementation of digitization to the operations. ISPE has pioneered to restructure Industry 4.0 to fit the Pharmaceutical Industry, which is now known as ISPE Pharma 4.0 Operating Model.

Pharma 4.0 Operating Model

Framework of ISPE Pharma 4.0 Operating Model


Pharma 4.0 enablers

  • Digital maturity
  • Data integrity by design

ICH derived enablers

  • Knowledge management and risk management


Pharma 4.0 elements

  • Resources
  • Information systems
  • Organization and processes
  • Culture

The above table depicts the basic structure and framework of the ISPE Pharma 4.0 Operating Model, which consists of two broad components:

  • Enablers
  • Elements

ICH defined Enablers: Knowledge Management and Risk Management

ICH defines knowledge management as a systematic approach to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes, and components.

The different sources of information include:

  • Product design and development
  • Technology transfer
  • Commercial manufacturing, etc.

The knowledge management of the product and product-related process needs to managed right from the product development through commercial manufacturing up to product discontinuation. It has to be digitalized in the form of  databases and should be connected directly to the raw data sources, which will ensure the data integrity of all GxP and non-GxP data, that  helps in making better choices and build regulatory confidence.

Various In-line, At-line, and On-line tools as used for :

  • Analysis of raw materials.
  • In-process monitoring
  • Final product analysis

These tools can be directly integrated into database systems for real-time data management.

ICH Q9 (Quality Risk Management), also known as the ICH Q9 model, is a fundamental guideline that describes the potential risks to quality that can be identified, analyzed and evaluated.

This guideline is supported by ICH Q10 (Pharmaceutical Quality Systems) which describes a model for an effective quality management system.

The ICH Q10 implementation has three main objectives:

  1. Attain Product Realisation
  2. Develop and Maintain a state of process control.
  3. Ensure continuous improvement.

ICH Q10 provides guidelines regarding critical quality attributes (CQAs) that should be within a specific range to ensure desired product quality. The variables, process parameters, and material attributes that affect the critical quality attributes are referred to as Critical Process Parameters (CPPs) and Critical Material Attributes (CMAs) respectively.

ICH Q12 appends on ICH Q10 to include those parameters which are not critical to quality but are responsible for the overall performance of the product. These attributes are known as Key Process Indicators (KPIs) and continuous efforts should be made to bring the KPIs under six sigma control.

Any excursions or changes in the CQAs, CPPs, CMAs, and KPIs should be communicated to the respective regulatory authorities; prior approval is required in certain cases before the implementation of the changes.

Pharma 4.0 Enablers: Digital Maturity and Data Integrity by Design

The first enabler in Pharma 4.0 to make an organization a smart factory is, Digital Maturity. It specifies the ability and the path of implementation of Pharma 4.0 for an organization. The model is developed in a way such that, an organization can perform gap assessment in terms of its position in digital maturity, improvisations in its capabilities, and based on what future capabilities would be. The basic requirement to achieve digital maturity is computerization and interconnectivity across all the quadrants of the operating models. After fulling these requirements, the organization can move towards advancement by capabilities like data visibility, predictive capacity, and adaptability.

  • Data visibility: A strategy where an organization can acquire, display, monitor, and analyze the data generated across all the sources in the organization.
  • Data Transparency: The ability to access the data no matter what generated it and where it is located.
  • Data Predictability and Adaptability: The ability of the data to predict future outcomes and improve on the predictability as more data is added to enhance the accuracy of the predictions.

These functions of the data help an organization to make a statistically calculated decision as they are based on real-time data.

ICH Q6 (Good Clinical Practices) defines data integrity as the extent to which data is complete, consistent, accurate, trustworthy, and reliable throughout the data lifecycle. The regulatory approval of the drug and all the related process are dependent on the quality and integrity of the submitted data. In the year 2016, USFDA issued a guideline, entitled “Data Integrity and Compliance with Drug cGMP”  that focuses on developing effective strategies for data integrity throughout the life of the drug product.

These strategies should be bases on quantitative risk assessments for patient safety.  Moreover, data integrity should be built into the products and related processes during the design and development; this could be done by introducing digitalization of data integrity known as ‘Data Integrity by Design’. When digitalization will be introduced, every process will have a defined workflow to avoid any silos of information and data integrity relates issues.

Pharma 4.0 Elements:


Resources of an organisation refer to the physical and intangible assets owned by an organization, majorly categorized into:

  • Human Resources
  • Machines
  • Products

The Machines employed in Pharma 4.0 should be highly advanced and developed based on Artificial Intelligence and Machine Learning. They would be highly automated and adaptive to the ever-changing business needs of the organization. These machines can be connected to PAT tools for in-line, online, and at-line monitoring during the manufacturing of the products. Such capabilities enable machines in taking their own decisions. But to run these machines, a new generation of highly skilled people is required, these people would be called Workforce 4.0. The success of Pharma 4.0 would largely be dependent on the engagement and continuous upskilling of Workforce 4.0 and the choice of Artificial Intelligence and Machine Learning Platform.


The information system is an integrated set of components for collecting, storing, and processing data and for providing information, knowledge, and digital products. By this means the components relate to each other. This integration forms a basis for:

  • How data is interfaced
  • How processes are Automated
  • How processes have the power for predictive analysis.

The predictive analysis enables the real-time release testing of the products known as “ ad hoc reporting”, which is already being used by some organizations.

The other benefit of integration into information systems is the preventive maintenance of equipment. The equipment takes ownership of its maintenance by analyzing daily data and let the potential maintenance activities be known in the first place and in some cases rectify the abnormalities, this reduces the equipment breakdown time significantly, thus increasing overall productivity. There is more potential area of integration into the information system, but they should adhere to global standards like GAMP5, ISO, etc.

Organization and Processes

An organizational structure needs to be developed which builds processes for substantiating prospective business challenges. Pharma 4.0 is a huge task for the organization and its outcomes are also uncertain, hence a sound and step-by-step organizational structure is required to be developed. The Organisational process needs to be developed across all elements of the holistic control strategy, such that each element functions collaboratively.


Culture refers to the shared beliefs and values of an organization that help achieve common organizational goals successfully. It should promote collaborative contributions as collaborations drive innovations. A culture where people understand the importance of each Pharma 4.0 element and which percolates down to each stage in the product lifecycle, from the early development to technology transfer and commercial manufacturing, should be developed.  New collaborations should be sought every time to improve on the existing capabilities and acquiring new capabilities. People should be encouraged to adapt to the new changes as upgradation is the requirement of sustenance in the ever-changing market.

Existing Control Strategy vs holistic Control Strategy

  • The existing control strategy was once a game change, which improved quality oversights in the manufacturing, however, to note it just reports quality, i.e, it can tell what has gone wrong, but it cannot predict when and what can go wrong. It puts process control by continuous monitoring of manufacturing processes for the process-related excursions.
  • The Holistic Control Strategy as described by ISPE is based on ICH and Pharma 4.0 enablers and elements that provide control over the production process to ensure a flexible, agile, sustainable, and reliable manufacturing system with lower risks to patients, processes, and products. However, its success depends on the mutual consensus between industry and regulatory agencies.

Barriers to Pharma 4.0

Even though the Pharma 4.0 model might initiate a new era of smart pharmaceutical manufacturing, there are several barriers to the adoption of this model.

 The main barriers involved are:

  • High cost of digitization
  • Time-consuming
  • Skilled and trained workforce
  • Uncertainty of the Outcomes

Despite all these barriers particularly the cost factor, Pharma 4.0 is going to be a reality and the desperate business need for sustainability. At Let’s Excel Analytics Solutions LLP we have developed cloud-based platform technologies that drastically cut down on digitalization costs. Hence, the barriers will be quickly offset by the tremendous increase in productivity and significant reductions in downtimes.


Pharma 4.0 digitalization is an imperative and inevitable transition that Pharmaceutical Industry is undergoing. To support the smooth transition to Pharma 4.0.

Curious to know about our automation accelerating machine learning platform ?